In a study of the protein p27, researchers at
Memorial Sloan-Kettering Cancer Center have confirmed the existence
of at least two types of prostate cancer. One is a more aggressive
form of the disease with a higher rate of recurrence and poorer
long-term survival. Researchers believe that this information can
help determine a patients prognosis as well as the best
treatment approach for that patient.
Researchers also discovered that p27 plays a distinct role in benign
prostate hyperplasia (BPH), which was found to be genetically
different from prostate cancer. This finding supports the thesis that
BPH is not a precursor for the development of prostate cancer.
The study, published in the September Journal of the National Cancer
Institute examined p27 protein levels in 130 tissue samples from
prostate cancer patients, normal men, and patients with BPH.
Levels of p27 Predict Disease Severity
The p27 protein, first discovered by study co-authors Dr. Joan
Massague, chairman of the Cell Biology Program at Memorial
Sloan-Kettering, and Dr. Andrew Koff of the Molecular Biology Program
is one of the proteins generically called a cell-cycle inhibitor. It
is a potential tumor suppressor. Normal prostate tissue has an
abundance of both the p27 protein and its messenger RNA (p27KIP1
mRNA), the intermediary between the gene and the protein. However,
both messenger and protein are undetectable in patients with BPH. In
contrast, patients with prostate cancer have abundant p27KIP1 mRNA
levels but variable p27 protein levels (high in some cases or very
low to undetectable in others). Investigators found that prostate
cancers with lower levels of p27 are more aggressive.
"Our study reinforces previous research that suggests that
prostate cancer can develop along two different pathways, one
involving the loss of p27 and the other using processes that
circumvent the growth-suppressive effects of p27," said Dr.
Carlos Cordon-Cardo, director of the Division of Molecular Pathology
at Memorial Sloan-Kettering and a co-author of the study. "At
the molecular level, we saw alterations resulting in two different
types of prostate cancer. Cancers with a lower level of p27 had a
biologically more aggressive disease associated with a higher rate of
recurrence and a greater risk of death."
The finding confirms collaborative research conducted by Memorial
Sloan-Kettering Cancer Center and the Norris Cancer Center at the
University of Southern California in Los Angeles. "Knowledge of
the prognosis of an individual patient can help determine who needs
additional therapy to improve their chance of cure," explained
Dr. Howard Scher, chief of the Genitourinary Oncology Service at
Memorial Sloan-Kettering and a co-author of the study.
BPH Not a Precursor of Prostate Cancer
In a related finding, built on the previous work of the study
co-authors, researchers determined that p27 was completely absent (at
both the gene messenger [mRNA] level and the protein level) from the
prostate tissue of patients with BPH. "This supports the
hypothesis that BPH is not a premalignant lesion in the development
of prostate cancer," said Dr. Scher.
Dr. Massague was the first to isolate and clone the p27 protein. Dr.
Koff was the first to produce genetically engineered mice without the
p27 gene. Studies in these "null" mice indicated that p27
plays a major role in the cells response to signals to stop
cell growth and promote growth arrest. The mice developed prostatic
hyperplasia similar to that found in human males, producing genetic
evidence that the loss of p27 expression in prostatic tissue of
elderly men may be causally linked to BPH.