What is the effect of patient and clinician decision support on genetic counseling uptake among women screened in the primary care setting for hereditary breast and ovarian cancer syndrome genetic testing eligibility?In this randomized clinical trial of 187 women and 67 clinicians, genetic counseling uptake was 19.8% for patients who received the decision aid vs 11.6% patients who did not, although this was not a statistically significant difference.In this randomized clinical trial, there was not a significant increase in genetic counseling uptake, although more than one-third of the ethnically diverse women enrolled to the intervention underwent genetic counseling. BRCA1/2 genetic testing compared with standard education alone.This cluster randomized clinical trial investigates the effects of patient and clinician decision support for  BRCA1/2 variants, the US Preventive Services Task Force recommends that primary care clinicians screen asymptomatic women for an increased risk of carrying a BRCA1/2 variant risk.To promote the identification of women carrying BRCA1/2 genetic testing compared with standard education alone.To examine the effects of patient and clinician decision support about BRCA1/2 genetic testing.This clustered randomized clinical trial was conducted at an academic medical center including 67 clinicians (unit of randomization) and 187 patients. Patient eligibility criteria included women aged 21 to 75 years with no history of breast or ovarian cancer, no prior genetic counseling or testing for hereditary breast and ovarian cancer syndrome (HBOC), and meeting family history criteria for RealRisks decision aid for patients and the Breast Cancer Risk Navigation Tool decision support for clinicians. Patients scheduled a visit with their clinician within 6 months of enrollment.The primary end point was genetic counseling uptake at 6 months. Secondary outcomes were genetic testing uptake at 6 and 24 months, decision-making measures  based upon patient surveys administered at baseline, 1 month, postclinic visit, and 6 months.P = .14). Genetic testing uptake within 6 months was also statistically nonsignificant . At 24 months, genetic testing uptake was 31 patients (30.7%) in intervention vs 18 patients (20.9%) in control (P = .14). Comparing decision-making measures between groups at baseline to 6 months, there were significant decreases in perceived breast cancer risk and in breast cancer worry .From December 2018 to February 2020, 187 evaluable patients  were enrolled  and 164 (87.8%) completed the trial. There was no significant difference in genetic counseling uptake at 6 months between the intervention group (20 patients [19.8%]) and control group (10 patients [11.6%]; difference, 8.2 percentage points; OR, 1.88 ; This randomized clinical trial did not find a significant increase in genetic counseling uptake among patients who received patient and clinician decision support vs those who received standard education, although more than one-third of the ethnically diverse women enrolled in the intervention underwent genetic counseling. These findings suggest that the main advantage for these high-risk women is the ability to opt for screening and preventive services to decrease their cancer risk.NCT03470402ClinicalTrials.gov Identifier:  We hypothesized that exposure to RealRisks and BNAV would lead to increased uptake of genetic counseling compared with patient education alone.To address these issues, we developed the RealRisks decision aid (DA) for women to screen for HBOC eligibility and the Breast Cancer Risk Navigation Tool (BNAV) for their clinicians.51 The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The study protocol can be found in The BEATRICE Study was an unblinded cluster randomized clinical trial that compared the effectiveness of RealRisks and BNAV, combined with standard educational materials with a control group of standard educational materials alone with clustering at the clinician level. For more details, the trial protocol is previously described.BRCA1/2 genetic testing based upon a validated family history screener,33 and being able to provide informed consent in English or Spanish.Participants were recruited from the outpatient clinics of CUIMC in New York City, providing a range of services, including internal medicine, family medicine, gynecology, and family planning. To be eligible, a clinician must be a physician, nurse practitioner, physician assistant, or nurse-midwife affiliated with study clinics and able to provide informed consent. Patient eligibility was having a clinician enrolled in the study, being aged 21 to 75 years, having no personal history of breast or ovarian cancer, having never received genetic counseling or testing for HBOC, meeting family history criteria for BRCA1/2 genetic testing, outlining breast and ovarian cancer risk management options and encouraging them to discuss referral to genetic counseling with their clinician. Patients in the study intervention received the patient-facing RealRisks DA coupled with their clinicians receiving the BNAV tool.All participating patients received standard educational materials in English or Spanish, including a brochure from our institution's breast cancer prevention clinic and educational materials from the Susan G. Komen Foundation on genes and breast cancer. Additionally, all patients received a letter informing them of their eligibility for BRCA1/2 variant based on the BRCAPRO model.53 Education is provided as information-dense  and information-light . Patient preferences are elicited using a slider tool. Women are also asked to indicate their intention to receive genetic testing. The patient’s risk, preference information, and intention are summarized for the patient in the patient action plan. Additional features to account for varying health and computer literacy include text to hover over to view definitions of key terms in the narrative, audio buttons, Spanish translations, and explanatory videos to navigate through the tool.Briefly, RealRisks is designed to improve a patient’s knowledge of breast cancer and personalized risk, as well as to support genetic testing decision-making. Upon logging into RealRisks, a patient is provided general education, and she is asked to enter her family history information into the tool. RealRisks then uses these data to calculate the patient’s breast cancer risk to provide personalized risk communication, tailored education, and decision support. Interactive games are used to communicate personalized 5-year and lifetime breast cancer risk and probability of carrying a 5 The framework and data flow that enables RealRisks and BNAV to exchange data have been previously described.55All clinicians had access to the BNAV tool through a link-out in the electronic health record (EHR) Ambulatory Medicine dashboard at CUIMC. BNAV consists of educational modules on breast cancer risk, genetic testing, and risk communication. For clinicians randomized to the intervention group, when their patients completed RealRisks, they were able to view personalized risk reports through a secure patient list within BNAV.57 subjective numeracy,58 acculturation,59 control preferences in decision-making,60 and trust in clinicians.61 Decision-making measures to assess genetic testing knowledge,62 decision conflict,63 perceived breast cancer risk,64 breast cancer worry,65 and decision self-efficacy66 were measured at all time points. Genetic counseling and testing end points were assessed by EHR review and abstraction. Research staff conducted the abstraction using a structured database format following training by a senior study investigator (K.D.C.). Patient clinic visits with their enrolled clinician were assessed by patient self-report and confirmed by EHR review. RealRisks utilization was calculated by dividing the number of RealRisks modules completed by the number of modules required, as confirmed by examining server logs.Study questionnaires were administered to patients at baseline, 1 month, postclinic visit, and 6 months after randomization. The baseline questionnaire assessed sociodemographics  and validated measures for ehealth and health literacy,65 decision self-efficacy,66 and decision conflict.63The primary outcome was HBOC genetic counseling uptake within 6 months after enrollment, as assessed by EHR logs. Secondarily, we assessed receipt of genetic counseling at 24 months, genetic testing at 6 months and 24 months, and patient reports of genetic testing knowledge, breast cancer worry,2 tests for categorical variables and t tests (or Wilcoxon rank-sum tests when nonparametric) for continuous variables. To compare 1- and 6-month survey variables between the groups and participant counseling and genetic testing uptake, we used linear regression models for continuous variables and simple or multiple logistic regression for categorical variables, with random effects to adjust for the clinician clusters. We calculated standard mean differences (SMDs) to estimate the effect of the intervention for continuous decision-making variables over time points. Data transformations were performed for skewed continuous outcomes, or nonparametric alternatives were used. These methods were also used to investigate the change in survey variables between baseline, 1 month, postclinic visit, and 6 months. For exploratory multivariate analyses investigating factors associated with EHR-confirmed genetic testing uptake, multilevel logistic regression models were fitted using generalized estimating equations with sandwich estimates of standard error and random effects adjustment for clinician clusters. Variables with a P < .10 in the bivariable tests were included in the models. Mean differences between randomization or tested and/or counseled groups were estimated with standard deviations, 95% CIs, and adjusted P values (to account for clustering by clinician). Overall, we found the intraclass correlation coefficient to be below 0.15. Odds ratios were generated for dichotomous outcomes, and 95% CIs were reported where appropriate. We analyzed data according to the intent-to-treat principle. Analyses were performed using SAS version 9.4 (SAS Institute) and R version 3.6.1  from January to October 2021.A sample of 190 women, assuming a 20% dropout rate and an intracluster correlation of less than 0.2, was planned to provide 90% power at alpha = .05 2-sided significance level to detect a 25% difference in the primary outcome. We examined frequency distributions of baseline and demographic characteristics of participants and compared between the 2 groups using χTo ensure missing data did not bias our findings, we performed sensitivity analyses for our primary outcome variable using an imputed data set created with the R package MICE (Multivariate Imputation by Chained Equations) version 3.13. We assumed a monotone missing data pattern, used predictive mean matching for missing values, and conducted 10 iterations. We first performed this analysis only for participants with partially missing data at a follow-up time point. We then created another data set involving participants who were entirely missing a survey at a particular time point. Results for the imputed data sets were analyzed using the same methods as the primary data set, and then sensitivity analyses were conducted comparing against the primary data set.67 Clinicians enrolled a range of 1 to 10 patients and a mean of 2.88 patients. Follow-up survey completion rates at 6 months were 85% in the intervention group and 88% in the control group. Demographics of participants who did not complete the 6-month survey were compared with participants completing the 6-month survey with no significant differences between groups. We also compared the demographics of participants who had a clinician visit with those not having a visit and found a significant difference in age, with older participants more likely to have a clinician visit.Trial enrollment began in December 2018, and follow-up survey data collection ended in August 2020. A total of 190 patients enrolled in the trial under 67 clinicians . Of 187 P = .14) (EHR-confirmed genetic counseling uptake within 6 months was not significantly different between the intervention and control groups. The intervention group had 20 patients (19.8%) with confirmed genetic counseling uptake vs 10 patients (11.6%) in the control group  .P = .31). At 24 months, EHR-confirmed genetic counseling was received by 37 patients (36.6%) in the intervention group vs 21 patients (24.4%) in the control group . Receipt of EHR-confirmed genetic testing at 24 months included 31 patients (30.7%) in the intervention group vs 18 patients (20.9%) in the control group   . Of the In terms of decision-making measures, decreases in breast cancer worry were greater in the intervention group from baseline to 6 months  and from baseline to postclinic visit  compared with the control group . GeneticP = .01). In the multivariable model, genetic testing intention , RealRisks utilization , and genetic testing knowledge  were significantly associated with genetic testing uptake  attended a genetic counseling appointment. Similar studies to identify women at risk for HBOC in primary care clinics69 and mammography centers70 show comparable rates of uptake of cancer genetic counseling and testing (10%-20%). Genetic testing uptake was higher in our study compared with previous studies; however, additional research to further improve uptake and the health of women with hereditary cancer risk is warranted.Although we did not observe a significant difference between groups in genetic counseling uptake, of the women identified and enrolled, 58 of 187 participants (31.0%) underwent genetic counseling, and 49 of 187 participants (26.2%) underwent genetic testing. These results suggest important clinical significance, since without our intervention these women would likely not have been identified to enable comprehensive cancer risk management. Other studies seeking to identify individuals at risk for HBOC have relied on validated screening instruments. For example, Arun et al71 Even after a referral, genetic counseling remains underutilized and disparities with respect to uptake exist.72 In a study of 72 women with low income screened for family history, Pasick et al73 found only 4.5% uptake of a free genetic counseling session when patients were asked to schedule the appointment themselves. This finding suggests that removing cost barriers may be insufficient to maximize uptake of genetic counseling.Clinician recommendation is often the first step toward uptake of genetic counseling, but a referral is less likely to occur among women in minoritized racial and ethnic groups and with patients with a lower level of education and limited health literacy.76 Decision-making about genetics is inherently different compared with other cancer screenings since genetic information can directly impact both the person undergoing testing and their biological family members. Yet, a recent systematic review found that resources to support decision-making about cancer genetic testing have an overemphasis on the cognitive aspects of making a decision  and lack tools that support patients through the decision-making process.77 Future research extending the use of DAs beyond the individual and clinician to better understand the family-based context in decisions to undergo genetic counseling and testing may be warranted.Cumulative evidence synthesized in a recent review suggests the importance of bidirectional influences in HBOC genetic counseling uptake, for example, among spousal and parent-child dyads.50 Additionally, our study simultaneously targeted both women and their clinicians.51 Our study reached a highly diverse population, with nearly half of the women recruited Hispanic and about 20% reporting a high school education or less. Reaching Hispanic women is vital because compared with non-Hispanic women, Hispanic women have lower awareness of genetic cancer risk assessment,78 lower testing uptake, and are more likely to have advanced-stage cancer at the time of diagnosis.84 In our study, we did not observe any racial and ethnic differences in genetic testing uptake, suggesting that DAs designed to be accessible to diverse populations and their clinicians play a role in ensuring equity of access among women eligible for HBOC genetic testing.85An important difference between our study and previous work is that we assessed a racially and ethnically diverse patient population with a patient-facing DA, which is available in English and Spanish and has been rigorously tested among women of varying health literacy and numeracy.89 Additional research is needed to assess factors that influence patient use and engagement and the true impact of DA implementation into clinical care.91 To increase RealRisks utilization, participants may have required additional engagement and support on how to access and navigate RealRisks. Therefore, we suggest this be addressed in future studies.Another strength of our study was the ability to track the actual use of the DA. We found among participants with EHR-confirmed genetic testing uptake, a higher level of RealRisks utilization was significantly associated with genetic testing uptake. This finding underscores the importance of DA utilization when they are implemented in clinical trials. Prior studies suggest that low fidelity to the intended use of DAs may underestimate their efficacy.This study has limitations, including documentation of our genetic counseling and testing end points from the EHR of a single institution. Study participants may have received these services elsewhere leading to an underestimation of the study intervention. Second, we did not directly link patient access to RealRisks with the scheduled appointment with their clinicians, which may have further dampened the effect of the study intervention. Third, we were not able to track the use of BNAV by enrolled clinicians. Lack of use may have undermined the effectiveness of the intervention. Fourth, the trial completion rate was 85%. Fifth, the study was designed assuming what we considered to be a conservative estimate of 25% group difference, but the observed difference was only 8% in the primary outcome. This may reflect that both groups received robust interventions, and utilization of RealRisks was suboptimal.In this cluster randomized trial, we did not observe increased genetic counseling uptake with the intervention, but we did find statistically significant increases in genetic testing knowledge and decreased breast cancer worry and perceived risk. Although differences in uptake were not significant, more than one-third of women in the intervention group and nearly a quarter of women in the control group underwent genetic counseling. The main advantage for these high-risk women is the ability to opt for screening and preventive services to decrease their cancer risk. Future studies should focus on DA implementation into clinical care and promoting patient engagement and use of the DA. Although it is unlikely that there will be a one size fits all approach, DAs such as RealRisks may play a role in ensuring equity of access among diverse women eligible for HBOC genetic testing.


This study aimed to investigate awareness of women living in the western region of Iran about warning signs and risk factors for ovarian cancer.This cross-sectional, descriptive-analytical study was conducted in Sanandaj and Kermanshah, Iran, 2020 and 2021. In this study, 1081 women aged 18–70 years were selected as the sample to fill out the electronic version of the Ovarian Cancer Awareness Measure (OCAM) to identify the significant variables of ovarian cancer warning signs and risk factors. The obtained data were statistically analyzed by descriptive statistics and ordinal logistic regression in SPSS 19.In this study, 60.9% of the participants had medium awareness of the subject. The results indicated that participants with higher educational attainment (P < 0.05) and those with a history of cancer (P < 0.001) showed higher knowledge of cancer. The lowest level of awareness of symptoms was associated with acute symptoms such as dysphagia  most days, persistent bloating, a sense of abdominal fullness or heaviness, and frequent urination. Moreover, the lowest awareness of risk factors was related to the history of IVF treatments and the application of talcum powder to the genital area.The study findings showed that women living in the western region of Iran have moderate awareness of ovarian cancer and insufficient knowledge of cancer warning signs; this suggests that it is necessary to train Iranian women to raise awareness of the signs and risk factors for ovarian cancer. Ovarian cancer is the third most common cancer and the third leading cause of cancer death among women in Low/Medium HDI Countries; it is considered one of the deadliest cancers. This disease affected 313,959 women and took the lives of 207,252 women worldwide in 2020. The most recent estimates reveal that the number of new cases of ovarian cancer per year will reach 371,000 by 2035; in addition, the number of women diagnosed with this disease will increase by 47% to 434,184 associated deaths reach 293,039 by 2040 [A variety of factors cause ovarian cancer, including lifestyle, environmental and genetic factors  SharifiaCurrently, the best biological diagnostic tool seems to be a combination of CA125 and HE4 levels to predict the risk of ovarian cancer in patients suspected of having benign ovarian tumors . HoweverContrary to popular belief, there is ample evidence that ovarian cancer has warning signs and symptoms, referred to as a "key message." Raising public awareness of ovarian cancer can be helpful in early diagnosis, and adequate knowledge of the disease's risk factors can help women recognize symptoms and encourage them to seek and adhere to medical treatments . One of Increasing women's awareness of cancer symptoms and risk factors while the incidence of its growth can effectively prevent that progression and reduce the cost of treatment imposed on the healthcare system . RaisingAccording to a literature review, no study has been conducted in Iran to assess the level of knowledge about ovarian cancer. Most studies on ovarian cancer in Iran have focused on the prevalence and risk factors.This cross-sectional, descriptive-analytical study was conducted on women in Kermanshah and Kurdistan provinces, Iran, from September 2020 to June 2021. The participants of this study were selected based on the multi-stage and network sampling methods. First, a list of cities and towns in Kermanshah and Kurdistan provinces was prepared. Then a quota was allocated to each province according to the number of cities, so three cities from Kurdistan Province and four from Kermanshah Province with a higher population were selected. Finally, Sanandaj, Marivan, and Saqez from Kurdistan Province and Kermanshah, Islamabad Gharb, Sarpol Zahab, and Javanroud from Kermanshah Province were selected for sampling. Midwives working in urban health centers in each city who were willing to participate in this study were briefed on the questionnaire and how it should be completed. After the online multi-stage sampling, the designed questionnaire's link was provided to midwives online via WhatsApp. After briefing them on the research objectives and procedures, the selected midwives then provided the link to the patients who were eligible to participate in the study. In cases where the participants could not complete the online form, the midwife asked the participant questions, and the answers were entered into the online form. Sampling was done at this stage by Convenience Sampling Method.1−α/2 + Zβ)2 p (1 − p)/d2 assuming a type-1 error of 0.05, power of 80%, and a proportion of women with the excellent knowledge of ovarian cancer (p) of 25% [The inclusion criteria were 18–70 years, no history of ovarian cancer, and willingness to participate in the study. The sampling process continued until the intended sample size was completed. Participants were asked to complete the questionnaire after expressing informed consent. The questionnaire was created in Google Forms, and the link was sent to participants via WhatsApp. The first section of the online questionnaire thoroughly briefed participants on the objectives and how to complete them. The participants were also assured that their information would be kept confidential. The sample size was calculated using the formula n = (Z) of 25% . The cal) of 25% , 15. ThiThe questionnaire was independently translated from English to Persian (translation forward) by two experts in the first step, after obtaining permission from the Ovarian Cancer Awareness Measure (OCAM). The research team then combined the two translation versions to create a single copy. Two specialists separately translated the final form into English (translation backward), and the research team merged the two English translations into a single copy . The tooTen experts  were asked to evaluate the validity of the questionnaire's qualitative and quantitative content. The questionnaire was then modified based on their comments on the grammar, vocabulary, necessity, syntax, collocation, and scoring system. The Likert scale was employed to assess relevance, simplicity, clarity, and necessity for each item, and the content validity ratio (CVR) was calculated quantitatively. The mean CVR was equal to 0.88, whereas the content validity index (CVI) was more significant than 0.79. Internal correlation and test–retest reliability were used to assess the stability of the questionnaire. The most commonly used method for determining internal correlation is Cronbach's alpha, which ranges from 0 to 1. It is appropriate to have an internal correlation more significant than 0.7 . CronbacA total of 1300 women volunteered for this study, but only 1081 completed the questionnaire.The sample size obtained is more than the sample size required for the study, and Incomplete questionnaires did not affect the study results.Six hundred five samples were from different cities in Kurdistan Province, with Sanandaj having the highest number of participants. Moreover, the highest number of participants in Kermanshah Province were from the city of Kermanshah. The mean age of participants was 32.63 ± 8.13 years. The majority of the participants  were Kurdish speakers. 58.3%( n: 631) were married, and most of them  had a bachelor's degree. The data showed that most participants  had no familial history of cancer  most days," "persistent bloating," "a sense of abdominal fullness or heaviness," and "frequent urination."In a study by Low et al. in the UK, the lowest level of awareness of warning signs was related to dysphagia  most days, a persistent sense of fullness, and frequent urination . ElshamiAdditionally, some symptoms of ovarian cancer may be confused with those of benign and more prevalent diseases, which can prevent timely visits for medical treatments . Early vThere are several reasons for not seeing or delaying seeing a doctor due to the cultural context of the western region of Iran, such as fear of cancer, shame, embarrassment, lack of health insurance and financial support, not seeing oneself at risk, belief in fate, lack of time due to family and career commitments, access to healthcare facilities, quality of health services, and forgetting , 27.Since the 5-year prognosis of this disease with early diagnosis in stages 1 and 2 is more than 70%, and whenever the diagnosis is delayed, survival rates are reduced to 20 to 40%. Therefore, early referral due to increasing awareness about warning signs and danger and how to treat the disease can effectively affect patient survival . The resThe main strength of this study is that it was one of the first studies to deal with women's awareness of the risk factors and warning signs of ovarian cancer and their knowledge of screening methods. However, this study had some limitations in terms of design and procedure. For example, the data were collected via an online questionnaire due to the COVID-19 pandemic. Although online data collection tools bring advantages such as lower cost , higher The study findings suggested that women living in the western region of Iran have moderate awareness of ovarian cancer and insufficient knowledge of its warning signs. The results showed that the lowest knowledge of warning signs was related to dysphagia  most days, persistent bloating, constant sense of abdominal fullness and heaviness, and frequent urination. Furthermore, the lowest knowledge of risk factors was related to the application of talcum powder to the genital area and history of IVF treatment. Given that the awareness of warning signs, risk factors, and age of cancer incidence can facilitate the early diagnosis of ovarian cancer, training women in these issues is necessary to raise awareness. The results of this study can also effectively evaluate and design prevention programs for ovarian cancer.


Breast cancer is one of the main causes of death in women worldwide. In women, breast cancer includes over half of all tumours caused by alcohol. This paper discusses both ethanol metabolism and the mechanisms of mammary tumourigenesis caused by alcohol. Numerous signalling pathways in neoplastic transformation following alcohol consumption in women have been presented. In addition, primary and secondary prevention, phytochemicals, synthetic chemicals, specific inhibitors of enzymes and selective receptor modulators have been described. Alcohol is the most consumed stimulant worldwide. Alcohol consumption has been related to different types of neoplasms in humans. There is epidemiological evidence that drinking alcohol elevates the risk of tumours in many organs, e.g. the oral cavity, larynx, oesophagus, liver, and pancreas. An increased risk of colorectal cancer has been observed in numerous studies .Alcohol consumption is a well-established risk factor for breast cancer in women. Breast cancer is a disease with an aetiology that includes dietary, lifestyle, and hormonal risk factors. Among these factors, alcohol consumption has been related to higher breast cancer risk .Globally, it was found that in 2016, there were 3.0 million yearly alcohol-attributable deaths  and 131.4 million disability-adjusted life years (DALYs) (UI 119.4–154.4). This corresponds to 5.3% of all deaths (UI 4.6–6.3) and 5.0% of all DALYs (UI 4.6–5.9). Alcohol consumption was a major risk factor for communicable, maternal, perinatal, and nutritional diseases, with a population-attributable fraction (PAF) of 3.3% (UI 1.9–5.6), noncommunicable diseases 4.3% (UI 3.6–5.1), and deaths 17.7% (14.3–23.0). Diseases caused by alcohol were more frequent among men than among women. The alcohol-attributable diseases were highest in Eastern Europe and the western, southern, and central sub-Saharan Africa regions as well as in countries with low human development indices (HDIs). A total of 52.4% of all alcohol-attributable deaths occurred in people younger than 60 years old [Over 2 million new cases of breast cancer are detected annually worldwide. Globally, the prevalence of breast cancer is 6.8 million cases. There is a consistent opinion that the intake of as little alcohol as less than 10–15 g per day leads to an elevated risk of breast cancer [It was demonstrated that in Europe in 2016, there were almost 80,000 cancer deaths caused by alcohol consumption . In the same year, almost 1.9 million cancer disability-adjusted life years lost were estimated  [Globally, the number of female deaths from breast cancer increased approximately 1.7 times  between 1990 and 2017. The age-standardized mortality rate (ASMR) of women’s breast tumours decreased by 0.59% (95% CI: 0.52–0.66%) annually. This decrease was mainly caused by the reduction in alcohol consumption and tobacco-associated female breast cancer [While the number of female breast cancer deaths caused by alcohol consumption rose from 44,200 in 1990 to 56,800 in 2017, and the ASMR values were reduced from 2.04/100,000 to 1.33/100,000 in that time. In 2017, alcohol consumption accounted for approximately 10% of total deaths from female breast cancer worldwide. This value was high in Western Europe, Latin America, and Australasia. In some regions, the ASMRs of female breast cancer associated with alcohol consumption were markedly reduced. The greatest reduction was observed in North America. In most developing countries, in the regions of South Asia, Central Asia, and the Caribbean, the ASMRs of breast cancer were significantly increased. In some European countries, including Denmark , Serbia , and Luxemburg , the ASMRs of breast cancer were high. The greatest values of this proportion were observed in Namibia, Sri Lanka, and Vietnam [g 10 g alcohol per day, the risk increased by 10.5% (relative risk (RR) = 1.10; 95% CI: 1.08–1.13) in total alcohol and 8.9%  in wine. For postmenopausal women, the risk increased by 11.1%  with every 10 g of the total alcohol increase. It was found that the breast cancer alcohol-associated percentage is higher in Europe than in North America and Asia. These data indicate that the effect of alcohol consumption on the incidence of breast cancer is mainly seen in ER + breast cancer. Quantitative analysis showed that drinking led to a significant risk of breast cancer, especially for postmenopausal women [In a meta-analysis of prospective cohort studies, 22 cohorts and 45,350 breast cancer cases were analysed. Women who were drinkers at the time with oestrogen receptor positivity (ER +) had an elevated risk compared to non-drinkers. A relationship between total alcohol and wine dose consumption and increased breast cancer risk was observed. When consuminal women .Similar results have been obtained in other studies. In the USA, 1484 cases of breast cancer were diagnosed (1190 invasive and 294 in situ) among 38,454 women. High alcohol consumption was related to a slight increase in breast cancer risk. For ≥ 30 g/day of alcohol versus none, the RRs were 1.32 (95% CI 0.96–1.82) for total breast cancer and 1.43 (95% CI 1.02–2.02) for invasive breast cancer. An elevated risk was limited to ER + and progesterone receptor (PR)-positive cancers. The RRs for an increase of 10 g/day of alcohol were 1.11 (95% CI 1.03–1.20) for ER + /PR + tumours (804 cases), 1.00 (95% CI 0.81–1.24) for ER + /PR − tumours (125 cases), and 0.99 (95% CI 0.82–1.20) for ER − /PR −  tumours (167 cases) [In another study, comprising 184,418 postmenopausal women, 5,461 breast cancer cases were registered. Total breast cancer was significantly connected with alcohol intake, even in the case of a moderate amount of alcohol (> 10 g/day). In the case where the amount of alcohol was > 35 g, the RRs were 1.35 (95% CI 1.17–1.56) for total breast cancer, 1.46 (95% CI 1.22–1.75) for ductal tumours, and 1.52 (95% CI 0.95–2.44) for lobular tumours. The RRs for ER + /PR + , ER + /PR − , and ER − /PR −  tumours were 1.46 (95% CI 1.12–1.91) for > 35 g/day, 1.13 (95% CI 0.73–1.77) for 20 g/day, and 1.21 (95% CI 0.79–1.84) for above 20 g/day, respectively [In women consuming 35–44 g per day, the alcohol RR of breast cancer was 1.32 (95% CI 1.19–1.45), whereas for women consuming ≥ 45 g per day, the alcohol RR of breast cancer was 1.46 (95% CI 1.33–1.61). The RR of breast tumours increased by 7.1% (95% CI 5.5–8.7%) for each additional 10 g of alcohol intake per day. In women with breast cancer and controls who did not consume alcohol, smoking did not raise the risk of breast cancer [The biotransformation of ethanol leads to the generation of metabolites that may cause cell function disturbance or cell death. Ethanol, as an enzymatic substrate, activates oxidative metabolic pathways or is incorporated into different chemical structures in non-oxidative reactions Fig. . The oxi+, hypoxanthine, xanthine, and its derivatives) significantly enhanced the metabolism of ethanol to acetaldehyde. This process is inhibited by allopurinol, but not by pyrazole [Ethanol metabolism proceeds via a two-stage process. In the first stage, acetaldehyde is created as a dominant metabolite; during the second stage, acetic acid is generated. The first stage of alcohol metabolism to acetaldehyde is catalysed by alcohol dehydrogenase , cytochrome P4502E1 , and catalase . In addition, ethanol is biotransformed to acetaldehyde and free radicals by molybdoflavoproteins, i.e. , xanthine dehydrogenase , xanthine oxidase , and/or aldehyde oxidase . Incubation of the cytosolic fraction of rat breast tissue containing XDH and XO with cosubstrates  and cellular damage. The role of CYP2E1 in alcoholic cancerogenesis is complex in that this enzyme is induced by ethanol, but ethanol is also an inhibitor of this enzyme .The induction of CYP2E1 by ethanol leads to the inactivation of retinoic acid (RA). Incubation of RA with the liver microsomal fraction from ethanol-treated rats resulted in the disappearance of RA and an increase in its polar metabolites, 18-hydroxy-RA and 4-oxo-RA levels. Both CYP2E1 antibody and chlormethiazole and allyl sulphide, specific inhibitors of CYP2E1, exert inhibitory effects on RA metabolism in the liver of rats. The metabolism of RA into polar metabolites was completely abolished by disulphiram and liarozole, nonspecific CYP2E1 inhibitors .Individuals differ in their ability to metabolize ethanol through genetic differences in ADH, the enzyme that catalyses the oxidation of approximately 80% ethanol to acetaldehyde in the liver. People differ in their ADH genotype . Genetic350Val and Arg272Gln, which determine the ADH1C*1 allele. 350Ile and 272Arg define the ADH1C*1 allele, whereas 272Gln and 350Val determine the ADH1C*2 allele [There are several categories of human ADH isoenzymes. The category I ADH enzymes, the products of ADH1A, ADH1B, and ADH1C genes , mostly participate in the biotransformation of ethanol. Among the category I ADH genes, especially ADH1B and ADH1C, polymorphic variants exist . Among A2 allele . Persons2 allele .The ADH1C gene is critical in cancer development because it has two alleles, a highly active allele ADH1C*1 and the less active allele ADH1C*2. It was demonstrated that the ADH1C*1 allele plays a crucial role in breast cancer risk in premenopausal women . In a stIn a study of 1047 breast cancer individuals and 1101 control subjects, it was demonstrated that breast cancer risk for fast metabolizers was strongly marked among premenopausal women. The OR in these women was 2.9 (95% CI 1.2–7.1), whereas in postmenopausal women, the OR was 1.8 (95% CI 0.9–3.8) . These dEpidemiological studies revealed that ADH1C alleles that lead to the accumulation of acetaldehyde in organisms can increase the risk of alcohol-derived cancers in the mammary gland. In a meta-analysis of a total of 6,159 cases and 5,732 controls in Caucasians, the pooled OR with 95% CI for breast cancer risk connected with ADH1C genotype was evaluated. The lack of an increased breast cancer risk was found in all genetic models . In the additive model, where patients were carrying the ADH1C*1 allele, an increased risk of breast cancer was not observed . These results indicate that ADH1C polymorphism may not be connected with breast cancer risk in Caucasians .+ proportion. The liver drives acetate to peripheral tissues, where it is metabolized into acetyl-CoA and then may be included in the tricarboxylic acid cycle or fatty acid synthesis.Acetaldehyde is rapidly metabolized into a nontoxic acetate by aldehyde dehydrogenase  in the liver. This reaction also increases the NADH/NADALDH is a mitochondrial and cytosolic heterogeneous enzyme (occurring as an isozyme) that participates in the biotransformation of endogenous and exogenous aldehydes. The mitochondrial ALDHs from the livers of rats, hamsters, and humans exhibit similar properties in the oxidation processes. However, the cytosolic ALDH levels in humans differ significantly from those in rodents. The Km value for acetaldehyde as a substrate for human LDH1 is approximately 12 times greater than those for rodents. In addition, ALDH1 is ten times less sensitive to disulphiram inhibition than rodent cytosolic ALDHs. ALDH2 is the most effective for the oxidation of acetaldehyde. This isozyme has the lowest Km (~ 0.2 µM) towards acetaldehyde as its substrate. It was suggested that ALDH2 is the only enzyme that oxidizes acetaldehyde in humans .ALDH2 is located in the mitochondrial matrix of hepatocytes. ALDH2 participates in detoxifying reactions, including the elimination of endogenous compounds such as 4-hydroxy-2-nonenal and malondialdehyde, the products of lipid peroxidation reactions. ALDH2 is also involved in the elimination of neurotransmitter metabolites such as 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycoaldehyde (DOPGAL) in the central nervous system. There is an inactivating point mutation in ALDH2 (named ALDH2*2) with low enzymatic activity . This enIn a study of 623 female breast cancer patients and 1845 control subjects from East Asia, it was found that alcohol consumption increased the risk of breast cancer regardless of ADH1B and ALDH2 genotypes. The polymorphism of ALDH2 was independently related to elevated breast cancer risk . The ADH1B polymorphism and the combination of ALDH2 and ADH1B polymorphisms did not show any relationship with breast cancer risk .From the point of view of potential health effects, the existence of the ALDH2*2 mutation in ALDH2, which occurs in approximately 560 million people in East Asia, or almost 8% of the world’s population, is important .Folate and alcohol are dietary factors that exert an impact on the risk of cancer development in humans. Alcoholism is associated with folate deficiency due to limited dietary folate consumption. Heavy alcohol intake decreases folate absorption, increases urinary folate excretion and inhibits key enzymes for one-carbon metabolism. Aberrant DNA methylation, caused by the deficiency of methyl donors, is considered a common negative effect of folate deficiency caused by ethanol. The negative effects of low consumption of nutrients that provide methyl groups and high intake of alcohol are additive. Low methionine and low folate diets coupled with alcohol intake could increase colorectal cancer risk in men .It was suggested that CYP2E1 and ALDH1 enzymes may be critical as causal factors in some tumours, especially in oral cancer. Chronic and high alcohol consumption leads to the induction of CYP2E1, which oxidizes ethanol to acetaldehyde. Acetaldehyde is a well-known carcinogen. This compound interferes with DNA methylation, synthesis and repair, and it also binds to protein and DNA to form stable adducts. It was found that S-adenosylmethionine (SAM), which is a product of folate biotransformation, regulates the catalytic activity of CYP2E1. It was hypothesized that high concentrations of folate may result in an increase in SAM levels, which inhibits the activity of CYP2E1 and causes a diminished production of acetaldehyde from ethanol. Within the ALDH1 family, two enzymes are critical in both ethanol and folate metabolism. ALDH1A1 transforms acetaldehyde into its nontoxic product, acetate. ALDH1L1, known as folate dehydrogenase (FDH), participates in the production of nucleotides. ALDH1L1 is downregulated in some physiological and pathological situations. On the other hand, its upregulation can cause antiproliferative effects. The other hypothesis states that folate interacts with one of the three known response elements that regulate gene expression to upregulate ALDH1A1 and ALDH1L1 expression to reduce acetaldehyde levels and ensure DNA stability .. This product exerted a neuroprotective effect against the neurotoxin 6-hydroxydopamine. Salsalinol significantly reduced the reactive oxygen species level in SH-SY5Y cells treated with H2O2 as well as the caspase activity. Serum levels of tumour necrosis factor-alpha (TNFα) and C-reactive protein (CRP) both served as indirect markers of neurotoxicity in salsolinol-treated rats and were not significantly different from the control animals [The electrophilic character of acetaldehyde ensures the possibility of participation in reactions with some endogenous compounds to produce various products, such as salsolinol. Salsolinol  is a product of the condensation reaction between acetaldehyde and dopamine. This compound, widely occurring in many edibles, did not show any necrotic effect on SH-SY5Y cells in vitro animals .Acetaldehyde reacts with amino groups and forms Schiff bases, altering the structures and functions of many proteins, including alkaline histones . Acetald2-ethyl-2'-deoxyguanosine, which is present in liver DNA obtained from ethanol-exposed rodents and in leucocytes obtained from human alcohol consumers. The carcinogenic relevance of this adduct is unclear because of the lack of evidence supporting its mutagenic activity in mammalian cells. Another DNA adduct, 1,N2-propano-2'-deoxyguanosine (PdG), can also be generated from acetaldehyde in the presence of histones and other basic compounds. PdG is responsible for genotoxic and mutagenic effects [Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges as well as chromosomal aberrations in human cells. The well-known adduct from acetaldehyde is N effects . In vitr effects , 34.Acetaldehyde reactivity also leads to covalent alterations in lipids and proteins by forming different adducts. Acetaldehyde lessens glutathione (GSH) levels and, consequently, cellular redox equilibrium by different mechanisms. These mechanisms may include, among other things, the nonenzymatic binding of GSH, a decrease in glutathione peroxidase activity, destruction of GSH into cysteinyl glycine, and disturbances of the transsulphuration process .2O2 and lipid peroxides. GSH is connected with different electrophilic compounds by glutathione S-transferase (GST). The products of these reactions are well eliminated from organisms. GSH biosynthesis is linked to the cellular methylation process through the transsulphuration pathway. The methylation process is essential for epigenetic gene regulation [GSH serves to protect cells against endogenous and exogenous electrophiles. This tripeptide is a cofactor for enzymes that metabolize Hgulation .Apart from oxidation, there are several non-oxidative reactions of ethanol that lead to the enzymatic conjugation of this chemical to endogenous metabolites such as glucuronic acid, sulphate phospholipids, and fatty acids. Ethyl glucuronide, ethyl sulphate, phosphatidylethanol and fatty acid ethyl esters are the products of these reactions. These conjugation reactions quantitatively represent a minor part of the biotransformation processes of ethanol in comparison with the oxidative reactions. These last reactions may have pathological significance due to the modification of metabolic processes , 37.Ethanol causes metabolic alterations that may lead to cancer development. According to the International Agency Research on Cancer (IARC), alcoholic beverages and acetaldehyde are classified in Group 1, i.e. substances carcinogenic to humans .Studies of alcohol in relation to breast cancer incidence have included hundreds of thousands of women. Evidence is consistent that alcohol consumption, even the intake of less than 10–50 g per day, leads to an increased risk of this disease. In addition, evidence shows that possible early indicators of risk, such as benign breast disease and increased breast density, are associated with alcohol consumption. Evidence is less strong for differences based on geographic region, beverage type, drinking pattern, or breast cancer subtype. Knowledge of breast cancer caused by alcohol as a risk factor is low in society [There are numerous risk factors for breast cancer. In a case–control study conducted in Poland, significant associations between some risk factors and breast cancer were observed. Obesity caused an elevated risk of mammary gland cancer in women compared to subjects with a BMI < 30 . Alcohol consumption ≤ 15 years of life led to a duplication of breast cancer risk . Women who breastfed for less than 3 months had a higher breast cancer risk . Women with basic education  and those living in rural areas  had an increased breast tumour risk .p trend < 0.001). The types of alcoholic beverages do not influence the cancerogenic risk level [In women, low to moderate alcohol intake increases the risk of some tumours. Every extra drink (a unit) systematically consumed per day is responsible for 11 breast cancers per 1000 women up to the age of 75 years. Increased alcohol drinking leads to an elevated risk of mammalian tumours  . The risk of this cancer type in women was not significantly associated with smoking [In a case–control study of 243 cases and 423 control subjects, it was found that women with a prior ductal carcinoma in situ diagnosis were at higher risk of invasive breast cancer. It was observed that drinkers with ductal carcinoma in situ smoking .The relationship between alcohol consumption and postmenopausal breast cancer risk among 87,724 women in the Women’s Health Initiative Observational Study prospective cohort from 1993 through 1998 was evaluated. A total of 2944 women with invasive breast cancer were diagnosed during follow-up through September 15, 2005. Alcohol consumption was positively related to the risk of invasive breast cancer overall, invasive lobular carcinoma, and hormone receptor-positive tumours. Women who consumed seven or more alcoholic beverages per week had an almost twofold increased risk of hormone receptor-positive invasive lobular carcinoma , but not a statistically significant increased risk of hormone receptor-positive invasive ductal carcinoma  compared with non-drinkers. The difference in HRs per drink per day among current drinkers was 1.15 (95% CI 1.01–1.32). The absolute rates of hormone receptor-positive lobular cancer among non-drinkers and current drinkers were 5.2 and 8.5/10,000 person-years, respectively, whereas for hormone receptor-positive ductal cancer, they were 15.2 and 17.9/10,000 person-years, respectively .Different patterns of alcohol drinking may have different effects on breast cancer development even when the total amount of alcohol intake is constant. The study was performed on a group of 9577 women (mean age 34 years), with a median follow-up of 11.8 years. Among 104,932 women-years of follow-up, 88 cases of breast cancer were diagnosed. Women in the binge drinking group had a higher risk of breast cancer  than those in the non-binge drinking category. In the stratified analysis, a twofold higher risk for premenopausal breast cancer was associated with a binge drinking habit  .In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, including a cohort of more than 360,000 women from 10 countries in Europe, the association between alcohol consumption and the risk of breast cancer was stronger for women with oestrogen receptor-positive tumours than for those with oestrogen receptor-negative tumours .1) and oestradiol (E2). The concentrations of dehydroepiandrosterone sulphate (DHEAS), testosterone, and sex hormone-binding globulin (SHBG) were not changed compared to those in non-drinking women [The relationship between alcohol consumption and oestrogen and androgen concentrations in the blood of postmenopausal women was evaluated in a cross-sectional study. It was found that women who consumed over 25 g of alcohol per day had higher levels of oestrone . When these women drank 30 g of alcohol per day, oestrogen was elevated by an average of 22.2% (significantly). Additionally, DHEAS levels were increased (significantly) by an average of 8.0% and 9.2% after intake of alcohol at doses of 15 g and 30 g daily, respectively. The concentrations of serum oestrone sulphate at week 4 versus week 8 across both doses of alcohol were similar. However, DHEAS concentrations were elevated significantly from week 4 to week 8 for all alcohol doses administered. Thus, the hormonal effects due to moderate alcohol intake are seen early, within 4 weeks from the start of alcohol consumption .p = 0.05) than in the no alcohol group. In the peri-ovulary phase, increases of 21.2% (p = 0.01) in plasma E1 levels, 27.5% (p = 0.01) in plasma E2 levels, and 31.9% (p = 0.009) in urinary E2 concentrations were observed. In the luteal phase, E1 levels in the urine increased by 15.2% (p = 0.05), E2 levels rose by 21.6% (p = 0.02), and oestriol levels increased by 29.1% (p = 0.03). The percent of bioavailable E2, defined by the sum of free E2 and albumin-bound E2, expressed as a percentage, did not change [A controlled-diet study lasting for six consecutive menstrual cycles in women with a history of regular menstrual cycles who consumed 30 g of ethanol (i.e. approximately two average drinks) per day was conducted. Plasma DHEAS levels were 7.0% higher in the follicular phase  was associated with an increased risk of the development of ER + tumours, irrespective of PR status compared to non-drinkers . The absolute rate of ER + breast cancer was 232 per 100,000 person-years among women in the highest category of alcohol consumption and 158 per 100,000 person-years among non-drinkers. No association between alcohol consumption and the risk of developing ER − tumours was observed. In addition, it was observed that there is a statistically significant interaction between alcohol consumption and the use of postmenopausal hormones and the risk for ER + PR + tumours .Oral ethanol administered at a dose of 0.225 g/kg body weight increased serum oestradiol levels significantly by 27–38% in premenopausal women, especially in the midphase of the menstrual cycle . It is wIn general, it has been confirmed that the consumption of alcohol is more strongly related to ER + breast cancers than ER− breast cancers , 55., culturing ER + human breast cancer cells in ethanol-containing medium was associated with an increase in their proliferation rate, ERα content and ER transcriptional activity. Since these changes were not observed in ER- breast cancer cells and because alcohol intake has been associated with an increased level of circulating oestrogens, it has been postulated that aromatase expression could be increased following ethanol exposure. The study shows a 1.3-fold increase in cell proliferation after 6 days of culture of MCF-7 cells in the presence of 0.1% ethanol. After a 6-day exposure to 0.1% ethanol, there was a 1.7-fold increase in ERα mRNA (not significant) and a 3.3-fold increase in ERα content (significant). In addition, a 2.4-fold increase in the aromatase mRNA level was demonstrated. These results are in agreement with the involvement of ER signalling in ethanol-induced stimulation of breast cancer cell proliferation [Finally, it has been reported that in vitroferation . Moreoveferation .Despite consistent evidence linking breast cancer to alcohol consumption, the mechanisms for carcinogenesis induced by alcohol are not completely known. Several ethanol actions have been hypothesized Fig. . These iAlcohol-associated carcinogenesis may be caused by smoking, diet, comorbid diseases, and genetic predisposition. An increase in endogenous oestrogen levels by alcohol drinking may lead to breast cancer. Patients with, among other things, some chronic liver diseases, gastroesophageal reflux disease and colorectal polyps are particularly susceptible to the tumourogenic action of ethanol. Carriers of the ALDH2*2 allele have a higher probability of alcohol-related oesophageal cancer. Carriers of ADH1C*1 homozygotes and methylenetetrahydrofolate reductase (MTHFR) 677CT variants are also at higher risk for alcohol-connected tumours. Factors such as poor oral hygiene, deficit of folate, vitamin B6, or methyl donors in diet or an excess of vitamin A and β-carotene in a meal also increase the risk of alcohol-associated tumours ., higher amounts of active MMP-2 and MMP-9 in their culture medium were observed. E2 induces growth in MMP-2 and MMP-9 levels. The anti-oestrogen ICI 182,780 inhibits the E2-induced increase in MMP-2 and MMP-9 secretion. In the case of ethanol exposure, this ER antagonist was only powerful on MMP-9 secretion. Although MMP-9 transcription in MCF-7 breast cancer cells was not sensitive to E2 or ethanol, MMP-2 transcription was stimulated by these compounds [In vitro studies using human tumour cells have identified signalling molecules that may contribute to the effects of alcohol, including ROS, acetaldehyde, matrix metalloproteases, ErbB2/Her2/Neu receptor tyrosine kinase, cytosolic protein kinases, adenylyl cyclase, E-cadherins, oestrogen receptors, and different transcription factors. The existing data suggest that the epidermal growth factor receptor (EGFR) tyrosine kinase may contribute to breast cancer development and progression . Amplifiompounds –63.It has recently been shown that epithelial-mesenchymal transition (EMT), a process by which cancer cells invade and migrate, and loss of cell‒cell adhesion molecules such as E-cadherin which have an increased level of mesenchymal proteins, e.g. vimentin, play a significant role in cancer progression and metastasis. Alcohol upregulated an EMT marker, vimentin, in colon and breast cancer cells. In colon and MCF-7 and MDA-MB-231 breast cancer cells, this compound caused an increase in MMP-2, MMP-7, and MMP-9 levels as well as cell migration. Alcohol also stimulated nuclear localization of a transcription factor (Snail) involved in tumour progression and malignancy. The snail level was significantly elevated in colonic tissue from alcoholics. Moreover, it was found that alcohol increased EGFR activation. EGFR inhibitors (e.g. AG1478 and TAPI-2) blocked Snail mRNA expression and alcohol-induced cell migration. These data indicate that cancer progression induced by alcohol through EMT activity is associated with an EGFR–Snail-mediated pathway .Alcohol stimulates mammary tumour growth by activating vascular endothelial growth factor (VEGF). In a mouse xerograph model of mammary tumours and a three-dimensional (3D) tumour/endothelial cell coculture system, it was discovered that alcohol stimulated tumour angiogenesis and accelerated tumour growth. In addition, alcohol induced VEGF expression in breast cancer cells in vitro and in vivo. The inhibition of VEGF by a specific inhibitor reduced both angiogenesis of tumours and alcohol-promoted tumour growth . VEGF noMetastasis is a process that includes intravasation and extravasation of cancer cells. The integrity of the vascular endothelial barrier plays a pivotal role in these processes. Ethanol at a concentration of 200 mg/dl disrupted endothelial monolayer integrity. This effect was reversible after the withdrawal of ethanol. The disruption of endothelial monolayer integrity led to growth in the invasion of cancer cells. Ethanol induces the endocytosis of VE-cadherin. VE-cadherin is an important component of the adherens junction and is responsible for vascular endothelial integrity. These results suggest that ethanol may simplify cancer metastasis by disjunction of the vascular endothelial monolayer ., increased aggressiveness of these cells by the mitogen-activated protein kinase (p38γMAPK/RhoC) pathway was observed. In this type of exposure to ethanol, a scattering of the examined cell colonies was observed. Moreover, increased colony formation and stimulation of cell invasion/migration were found. In addition, the population of cancer stem-cell like cells (CSCs) increased. The above-mentioned cancer cells treated with ethanol in vitro manifested a higher increase in velocity and metastasis in mice in vivo [In breast cancer cells  chronically exposed to ethanol in vitro in vivo .p38γ is one of the isoforms of a p38 MAPK enzyme that includes the following isoforms: p38α, p38β, p38γ and p38δ. These p38 MAPKs are kinases of serine/threonine. These enzymes are activated by different cellular and environmental factors, as well as other inflammatory cytokines. It was found that p38γ MAPK may participate in carcinogenesis. However, the molecular mechanism of its action is unknown. It was shown that p38γ MAPK leads to EMT growth in breast cancer cells. EMT facilitates cancer cell progression and metastasis and participates in the regulation of CSCs. CSCs have a self-renewal capacity and are resistant to chemotherapy. While overexpression of p38γ MAPK activated EMT, its downregulation depressed EMT. Whereas p38γ MAPK increased the CSC number, knockdown of p38γ MAPK decreased the CSC ratio in breast cancer cells. MicroRNA-200b (miR-200b) was downstream of p38γ MAPK and negatively regulated by p38γ MAPK. miR-200b inhibited p38γ MAPK-induced EMT, while miR-200b inhibitors stimulated EMT. The regulation of miR-200b expression by p38γ MAPK proceeds through inhibiting GATA3. GATA3 is a transcription factor that regulates miR-200b expression. p38γ MAPK induces GATA3 and leads to its proteasome-dependent degradation; p38γ MAPK participates in the regulation of the CSC population, migration/invasion, tumourigenesis and cell transformation. EMT plays a crucial role in cancer progression, the dissemination of cancer cells from solid tumours and the formation of metastases. During the process of EMT, epithelial cancer cells achieve molecular characteristics that facilitate the loss of epithelial features and acquisition of the mesenchymal phenotype. Such a transformation leads to cancer cell migration and invasion –71.Alcohol causes migration and invasion of triple-negative breast cancer cells (TNBC) through activation of p38 MAPK and JNK. These cells are a subtype of breast tumours that lack ER and PR hormone receptors and HER2 receptor expression. It has been shown that alcohol at low concentrations (0.025–0.1%) in MDA-MB-231 and MDA-MB-468 cell lines caused cell proliferation, migration, and invasion. Both of these cell lines represent TNBC. The changes observed were induced by ROS production, activation of p38 MAPK, and JNK phosphorylation. Alcohol exposure activated the nuclear transcription factor NF-кB and increased the transcription of NF-кB-targeted genes. In TNBC cells, acetaldehyde, a major alcohol metabolite, induced cell migration and invasion and increased the phosphorylation of p38, JNK, and NF-кBα in a manner similar to ethanol .The induction and development of female breast cancer are conditioned by different factors. These factors include alcohol consumption, precocious puberty, late menopause, first pregnancy in late age, a short period of breastfeeding, use of combined oestrogen and synthetic progestogen hormonal therapy, a high-fat diet, and little or lack of physical exercise. The elimination of some of these factors, as a primary prevention, may protect against morbidity and mortality caused by breast cancer , 74. TheSome compounds, particularly phytochemicals present in food, drinks, and dietary supplements, which have potent inhibitory activity on the enzymes of ethanol metabolism to acetaldehyde , may be Cimicifuga species. Actein treatment of MDA-MB-231 human breast cancer cells (oestrogen receptor negative) in vitro significantly reduced cell proliferation, migration, and motility, caused G1 phase cell cycle arrest and suppressed MMP protein expression. Moreover, actein blocked the adhesion of breast cancer cells to collagen and decreased the level of integrins. Exposure to this compound led to downregulation of the levels of EGFR, AKT and NF-κB signalling proteins. The in vivo study demonstrated that actein significantly reduced the number of zebrafish embryos with migrated cells by 74% and decreased the number of migrated cells in embryos. Actein is a novel anti-migration natural compound with anti-metastatic activity [Actein, as a natural compound, is obtained from the root of activity .Several phytochemicals, especially polyphenols, exert inhibitory action on enzymes responsible for acetaldehyde biosynthesis present in mammary tissue –81. The ALDH activity in the mammary gland is several times lower than that in the liver. Mitochondrial ALDH activity is subject to the inhibitory action of 4-hydroxy-2-nonenal, the lipid peroxidation byproduct, which is both a substrate and an inhibitor of this enzyme . Thus, wThe administration of cysteine may diminish acetaldehyde accumulation in the mammary gland by generating 2-methylthiazolidene-4-carboxylic acid, a stable adduct . N-AcetyThe carcinogenic effect of ethanol may also exist as the result of catechol-O-methyltransferase (COMT) detoxifying pathway dysfunction. COMT participates in the conjugation of catechol oestrogens in the presence of S-adenosylmethionine (SAM), folate, and vitamins B6 and B12. SAM administration may diminish oxidative stress by GSH synthesis, attenuate the inflammatory process by decreasing TNF-α levels, and increase the biosynthesis of interleukin-10 .In the transmethylation reaction, S-adenosylhomocysteine (SAH) is produced with the participation of SAM. SAH is a potent inhibitor of the methylation reaction. Chronic ethanol drinking depleted the hepatic level of SAM, increased the plasma level of homocysteine and hepatic concentration of SAH, and reduced the folate plasma level in animals and humans. Administration of SAM causes the restoration of the hepatic level of GSH reduced by alcohol . SAM admIn the studies of many selected Chinese medical plants, a highly positive correlation between antioxidant capacities, expressed in inhibition of xanthine oxidase (XO) and neutralization of the superoxide radical, and total phenolic content has been found , 91, 92.In another study, it was found that apigenin, galangin, kaempferol, quercetin, genistein and resveratrol potently inhibited the XO enzyme among 30 bioactive compounds present in the edible food plants tested. Flavonoids exhibit highest, anthocyanins and hydroxycinnamic acids moderate, while maslinic acid, ellagic acid, salicylic acid, -gingerol−) production. The inhibitory activity of alk(en)yl phenols was divided into three types of processes. The first is XO activity inhibition, the second is reduction of O2− production and the third is O2− scavenging [Recently, it was revealed that the inhibitory activity of alk(en)yl phenols, present in many edible plants, towards XO is related to both the hydroxy group arrangement in the phenol moiety and the alk(en)yl chains. The inhibitory activity of these compounds in relation to XO is expressed as a combination of uric acid synthesis inhibition and suppression of superoxide anion , such as lasofoxifene, raloxifene, and tamoxifen, and aromatase inhibitors, i.e. anastrozole, letrozole, and exemestane, are drugs applied in breast cancer therapy. Tamoxifen and raloxifene reduced the morbidity and mortality from breast cancer. Promising results of aromatase inhibitor tests indicate that these compounds are efficient in the prevention of ER + breast cancer. Instead, present-day investigations are concentrated on elaborating preventive therapies for other subtypes of breast cancer, such as HER2 + and TNBC. HER2 + breast cancers are at present treated with trastuzumab and lapatinib. A few drugs, such as poly(ADP-ribose) polymerase inhibitors, vitamin D, and retinoids, are currently being examined for the prevention of TNBC . The othExemestane, an aromatase inhibitor, has been examined for breast cancer prevention in postmenopausal females. In a group of 4,560 high-risk postmenopausal females treated with exemestane 25 mg daily for approximately three years, there was a 65% relative decrease in the annual occurrence of invasive breast cancer when compared with the placebo. In addition, a 53% decrease in invasive plus noninvasive breast cancer was observed. Adverse effects from exemestane are generally mild, with the most common being diarrhoea, joint pain, and menopausal symptoms. It is crucial that exemestane did not increase the risks of endometrial cancer, thromboembolism, cardiovascular disorders, or cataracts. Instead, joint stiffness and arthralgia were observed more frequently than in the case of tamoxifen and raloxifene .It was estimated that practically half of the women at high and moderate risk of breast cancer could benefit from the application of current therapy, i.e. exemestane, raloxifene, antrazole, and tamoxifen. Moreover, controlling body weight, exercise and moderating alcohol consumption in all women could diminish breast tumour risk by approximately 30% .It was found that breast cancer risk increased by 7% to 10% for each additional daily alcohol consumption. A drink is half a pint of 4% alcohol content beer or cider or 25 mL of 40% spirits, while a small 125-mL glass of 12% wine is 1.5 drinks. Females who consume four to nine drinks weekly are 15% more likely to develop breast cancer than non-drinkers . It was Carcinogenic prevention includes not only middle- and late-aged women, but also younger women after menarche . For carThis review presents information on important findings concerning ethanol metabolism, ethanol breast cancer development, and its prevention.Most data indicate that alcohol consumption increases the risk of mammary gland tumour in both pre- and postmenopausal women. Worldwide, the number of deaths from female breast cancer increases. The data indicate that alcohol consumption is mainly involved in the incidence in ER + and/or PR + breast cancer. Increasing alcohol consumption was related to a rise in breast cancer risk. Different manners and amounts of alcohol consumption may have varied influences on breast cancer development.Ethanol consumption activates metabolic pathways in an oxidative way or incorporates this compound into different chemical structures in non-oxidative reactions. The oxidative metabolism of ethanol predominates over the non-oxidative metabolism. Ethanol metabolism includes a two-stage process. Under the first stage, acetaldehyde, as a primary metabolite, is generated; during the second stage, acetic acid is produced. While the first stage is metabolic activation, the second stage is detoxification.The metabolism of ethanol is catalysed by numerous enzymes, including ADH, CYP2E1, CAT, XOR, AO, and ALDH. These enzymes most often exist as different classes of isoenzymes that cause differentiation in individual and racial ethanol metabolism and a variety of breast cancer risks.The mechanisms by which ethanol induces carcinogenesis include oxidative stress, altered DNA methylation and interaction with retinoid metabolism. In addition, signalling molecules such as acetaldehyde, ROS, matrix metalloproteinases, cytosolic protein kinases, E-cadherins, and different transcription factors may contribute to the carcinogenic effects of ethanol. EGFR tyrosine kinase may contribute to breast cancer development and progression. Ethanol stimulates invasion of breast cancer by overexpression of ErbB2, which is positively associated with elevated levels of matrix metalloproteinases. The activation of metalloproteinases is dependent on c-Jun, JNK, and ROS. Ethanol activates VEGF and EMT, which play a significant role in cancer progression and metastasis. This xenobiotic causes migration and invasion of triple-negative breast cancer cells through activation of p38MAPK and JNK. Ethanol activates the nuclear transcription factor and increases the transcription of NF-κB-targeted genes.There are primary and secondary prevention strategies that may improve rates of morbidity and mortality from breast cancer. Some phytochemicals present in food, drinks, and dietary supplements that exert an inhibitory effect on the enzymes of ethanol metabolism to acetaldehyde may be recognized as prevention agents. The administration of cysteine, NAC, and SAM may diminish acetaldehyde accumulation in mammary tissues and may stimulate catechol oestrogens’ conjugation by COMT. The compounds that exert their action on the ER and aromatase blocking agents inhibit the ER or oestrogen-activated pathways. The selective therapies currently tested include tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, antibody‒drug conjugates, and monoclonal antibodies.


Individuals who experience early life adversity are at an increased risk for chronic disease later in life. Less is known about how early life factors are associated with cancer susceptibility. Here, we use a life history framework to test whether early life adversity increases the risk of breast cancer. We predict that early life adversity can shift investment in somatic maintenance and accelerate the timing of reproduction, which may mediate or interact with the risk of breast cancer.We use population-wide data from the Utah Population Database (UPDB) and Utah Cancer Registry, leading to 24 957 cases of women diagnosed with breast cancer spanning 20 years (1990–2010) and 124 785 age-matched controls. We generated a cumulative early life adversity summation score to evaluate the interaction (moderation) and mediation between early life adversity, reproductive history and their association with breast cancer risk.Our analyses led to three key findings: (i) more early life adversity, when considered as a main effect, accelerates the time to first birth and death, (ii) early age at first birth and high parity decreases the risk of breast cancer and (iii) we find no association between early adversity and breast cancer risk either as a main effect or in its interaction with reproductive history.Early adversity elevates the risk of overall mortality through mechanisms other than breast cancer risk. This suggests early life factors can generate different effects on health. Future work should incorporate more complex view of life history patterns, including multiple life stages, when making predictions about cancer susceptibility. Individuals with multiple adverse early life events are at an increased risk for poor late-onset health outcomes, including inactivity, obesity, diabetes, cancer, heart disease, mental ill health and problematic alcohol or drug use . AdverseCurrently, there are multiple theoretical frameworks for understanding this link between adverse conditions early in life and adult health and survival, including allostatic load , 8 and aTo test these predictions, we focus on breast cancer, the most commonly diagnosed cancer in women in the USA and globally  and the The accumulation of early adverse life events may set individuals on a distinct life history trajectory leading to more morbidity and mortality later in life . ExposurHere, we investigate the roles of early life adversity and accelerated reproduction in shaping breast cancer risk. We examine whether individuals who experience high childhood adversity have an increased risk for breast cancer and then we examine whether there is mediation and effect moderation (interaction) between adversity and reproductive factors and breast cancer risk. We predict that high early life adversity is associated with the risk for breast cancer, beyond the increase in risk that comes from lower fertility and delayed reproduction. In other words, adversity and lower/delayed fertility should have synergistic effects on breast cancer risk. Higher fertility and earlier reproduction would be expected to decrease the risk of breast cancer in individuals who experienced greater early adversity.To investigate the association between cumulative early life adversity and breast cancer risk, we leveraged linked data from the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR), which have extensive demographic and medical information on individuals across multiple generations. To test for the effects of early adversity, we generated a novel cumulative adversity score (CAS), using demographic and administrative data. This is, to our knowledge, the first study to look at the interaction between early adversity measures and reproductive variables in breast cancer risk.This study utilizes data drawn from the UPDB. The UPDB is one of the world’s richest sources of linked population-based information for demographic, genetic and epidemiological studies. UPDB has supported numerous biomedical investigations in large part because of its size, inclusion of multi-generational pedigrees and linkages to numerous data sources. The UPDB contains data on over 11 million individuals from the late 18th century to the present. UPDB data represent Utah’s population that appears in administrative and historical records. The holdings of the data grow due to longstanding efforts to update records as they become available including statewide birth and death certificates, hospitalizations, ambulatory surgeries and driver licenses. UPDB creates and maintains links between the database and the medical records held by the two largest healthcare providers in Utah as well as Medicare claims. The multigenerational pedigrees representing Utah’s founders and their descendants were constructed based on data provided by the Genealogical Society of Utah (GSU). These pedigrees spanning the past century have been expanded extensively based on vital records and, together with the GSU data, form the basis of the deep genealogical structure of the UPDB. The overall structure of the UPDB provides the basis for identifying events and conditions that span a person’s lifetime including births and deaths among kin as well as family structure and socioeconomic status. The UPDB comprehensively links statewide cancer incidence data from the UCR, a National Cancer Institute supported Surveillance, Epidemiology, and End Result (SEER) registry that collects data on all incident cancers in Utah except non-melanoma skin cancer. The UCR started in 1966 and became a SEER registry in 1973. This study has been approved by the University of Utah’s Resource for Genetic and Epidemiologic Research and its Institutional Review Board. The UPDB has been used for a wide range of population-based studies . To acceWe developed a new measure designed to capture stressors across the life course that may affect later life health. The CAS is based on six sociodemographic measures  includinParent’s age at ego birth was determined by using the ego’s birth year. An indicator variable was created to flag whether the mother was 18 years or younger at the time of ego’s birth.The patient’s childhood socio-economic status (SES) was determined using both parents’ Socio-Economic Index (SEI) and Nam Powers scores. The higher of either parents’ SEI and Nam Power’s scores were recorded for the ego.We recorded the number of siblings known to have died when ego was <18 years old.We recorded whether the parent died before the ego was 10 years old, and whether the parent was still alive when the ego turned 18. We determined whether the parent was still alive when the ego was diagnosed using the parent’s last living date and the ego’s date of diagnosis.and was in the lowest SES quartile. We summed all points together to create the CAS. Finally, we mean-centered CAS in order to address collinearity concerns when CAS is used in an interaction with reproductive variables.We then developed a CAS to summarize the early life adversity for each individual. We assigned a point for each adverse event. This approach used the presence or absence of adverse events. If data were missing with respect to a specific component of CAS, we assumed it to be absent for that particular adverse event. These events were: (i) ego’s mother died before ego was 10 years old, (ii) ego’s father died before ego was 10 years old, (iii) ego was born to young mother (<18 years old), (iv) any sibling death, (v) ego’s socio-economic status was in bottom 25% of all records and (vi) if ego resided in a household with more than five siblings Categorical variables were used to capture reproductive history. AFB was classified in a manner similar to previously published cut-offs , which iTo assess the relationship between early life adversity and breast cancer risk, we used data from UPDB, which allowed us to identify 24 957 women diagnosed with breast cancer and 124 785 age-matched controls. In order to observe the full period of fecundity, we only included women who survived to at least age 45 in this study. After imposing data eligibility restrictions, we report a total of 86 881 individuals in the dataset, with 14 859 breast cancer cases and 72 022 controls. After filtering, birth years ranged from 1910 to 1970 and the median age of death was 80 years . Median Reproductive history above for more details). We estimated the relationship between the CAS, reproductive history and whether there was a breast cancer diagnoses (i.e. cases vs controls). We used nested GLM models to fully explore the relationship between CAS and reproductive history in two distinct ways: (i) complete dataset  and (ii) parous dataset . Results based on the parous subset are published in Cox proportional hazards models were used first to estimate the association between CAS and all-cause mortality , 34. TheWomen in this dataset were born between 1910 and 1970, with ages ranging from 26 to 107 years . There wN = 86 881; HR = 1.05, P < 0.001 (P < 0.001), but that it is not associated with parity . Next, h parity .n ≤ 2 children) is associated with an increased risk of breast cancer  and low parity (less than two children) are in the highest risk category for breast cancer studied here. Because of later reproduction and lower parity compared with our human ancestors, human females living in large-scale, industrialized societies, have substantially more menstrual cycles, with estimates as high as four times as many menstrual cycles in a lifetime , 55. EndIn addition to hormone exposure, the relationship between early AFB and lower breast cancer risk could be due to early terminal differentiation of mammary cells induced by that first pregnancy , 57. EarWe did not find a direct association between adverse childhood events and risk of developing breast cancer, but we did find that greater childhood adversity was associated with earlier reproduction and higher mortality. We conclude that these results are consistent with both a life history framework , 13, 27 While previous studies have found that stressful early life events are associated with an increased cancer risk later in life , 3, 21 fCurrently, there is a gap in knowledge about why breast cancer subtypes have different risk profiles. Reproductive patterns have little influence on ER-negative breast cancer risk . ER-negaOur findings contribute to the growing literature on adverse early life conditions and their association with poor health and survival in adulthood. Our work demonstrates that data from administrative records, which reflect familial and social structural circumstances, such as low SES and parental or sibling death, can produce robust measures to predict the risk of early mortality. We find that early life adversity is not associated with breast cancer risk while reproductive factors (delayed reproduction and low parity) are associated with breast cancer diagnosis later life. This suggests that life history theory does not on its own explain breast cancer risk patterns and that evolutionary mismatch explanations  should be considered as well. To the extent that early life adversity does affect breast cancer risk, it may be that this is mediated through reproductive factors, such as an association with early reproduction and higher parity, which then indirectly provide protective benefits against the disease. Future work can help disentangle the roles of these various factors by investigating the underlying molecular mechanisms and taking into account the heterogeneity of breast cancer types.EMPH online.eoac034_Supplementary_DataClick here for additional data file.