Study of Protein Reveals Two Different Types of Prostate Cancer

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 patient’s 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.