Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer
Robert T. Dauchy, Shulin Xiang, Lulu Mao, Samantha Brimer, Melissa A. Wren, Lin Yuan, Muralidharan Anbalagan, Adam Hauch, Tripp Frasch, Brian G. Rowan, David E. Blask, and Steven M. Hill
Cancer Res. 2014 Aug 1;74(15):4099-110
Two-thirds to three-quarters of breast cancers are hormone receptor positive – meaning they express the estrogen or progesterone receptor – and so can be treated with endocrine therapies such as tamoxifen or aromatase inhibitors. On the whole, this is good news for the patient. The endocrine therapies are very good at choking off the hormone signals that make the cancer grow, and so are good at keeping the cancer in check. If the cancer is not hormone dependent, then this avenue of therapy is not an option.
Endocrine therapy works by removing the source of estrogen, or preventing it from interacting with its receptor, everywhere in the body. It is substantially contributing to the longer life expectancy of breast cancer patients. However, as patients live longer, it is more common to see reoccurrence of the cancer, once it has escaped the hormone suppressive therapy. When it does, it is more aggressive and often metastatic.
Analyses of the cancers that come back shows that they have learned to live without the external estrogen signal that tamoxifen or aromatase inhibitors eradicated. How do they do that? Hormone receptors switch on specific signals inside the cells to fulfill their function. But there are other, alternate ways to switch these signals on too – and it is by activating these other ways that the recurrent breast cancer cells have stepped around the hormone therapy and resumed their growth. Broadly speaking the alternate pathways are kinase pathways – a kinase is an enzyme that decorates other molecule with phosphate, and this constitutes typically a “go” signal – it promotes growth, or movement for example, depending on the proteins involved.
So how does this relate to darkness? Well, it turns out that melatonin, a hormone that is produced in animals when they are in the dark and controls the night-day cycle, is an inhibitor of some of these same alternate kinase signals. In the case of breast cancer patients, melatonin therefore cooperates with endocrine therapy to suppress breast cancer growth.
One way to think of this, is that melatonin helps your body sleep by down regulating kinase activity, and this effect is also felt by the cancer cells. When these cancer cells are simultaneously deprived of estrogen, the suppression of cancer growth is enhanced – the cancer cells remain dormant, or maybe are even killed. In contrast, if you are exposed to light all the time, even relatively small amounts, then the kinase pathways remain more active, and the threshold to overcome the estrogen deprivation is more easily reached. Cancer cells may awaken more easily and even overcome the hormone deprivation.
Dauchy et al modeled this in rats, and were able to show the biology behind it. They grew experimental breast cancers in rats, and either let the rats sleep in the dark or with a little light. Then some rats were treated with tamoxifen, and tumor growth was followed. Keeping the lights on negated the effect of tamoxifen. Convincingly when they gave melatonin as a drug to the rats that were sleeping in the light, they were able to restore the effectiveness of the tamoxifen. They did a lot of additional biology – looking at the kinase signaling, and the behavior of the tumor cells – to figure out the mechanism behind this observation.
So what does it mean to a breast cancer patient on endocrine therapy? Perhaps most simply, it is important to get a good nights sleep, in the dark. How much light should you worry about? Dr. Hill, the senior author of the study and leader of the research group that undertook it, has said that amount of light the rats in this study were exposed to was “roughly equivalent to faint light coming under a door” or “the amount of light that comes in the bedroom window from a street light”.
Should you take your tamoxifen or aromatase inhibitor at a particular time of the day? While these data in rats are pretty suggestive, we don’t have human data yet, so that is a major caveat. Furthermore, the endocrine therapy will have its own rhythm depending on the rate of uptake, metabolism and excretion of the drug, and so it is not easy to predict when the ideal time is. Clearly, as the authors of Dauchy et al indicate, more research on these specifics is needed.
Having said that…
… and on a personal note, I am making changes based on this research. Here is my thinking:
- We know that tamoxifen has a peak plasma concentration 3-6 hours after administration, and a half life between 7 and 14 hours.
- Peak melatonin levels are reached about midway through the dark cycle, and if you sleep 7-8 hours a night, that would be about 3-4 hours after you go to bed.
- Taking the tamoxifen at bed time would therefore give you a maximum of both its active metabolite and melatonin around the same time, and based on the rat model here, maximum impact on estrogen dependent breast cancer cells.
One concern about taking tamoxifen at night is that occasionally I have a glass of wine, or a beer, and since liver metabolism is critical to conversion of tamoxifen to its active form, that crossed my mind, However, the metabolic pathways for alcohol and tamoxifen are different, and so I think the occasional drink will not reduce its effectiveness.