Researchers at Cleveland Clinic have discovered that a gene – known as an androgen receptor (AR) – is found in both prostate and breast cancers yet has opposite effects on these diseases.
In prostate cancer, the AR gene promotes cancer growth when the gene is “turned on.” In breast cancer, the AR gene promotes cancer growth when the gene is “turned off,” as is often the case after menopause, when AR production ceases in women.
What this means is that treating prostate and breast cancers require completely opposite approaches to AR. In treating prostate cancer, the strategy should be to block AR; in breast cancer, the strategy should be to support AR production.
Researchers from Cleveland Clinic’s Lerner Research Institute, including Charis Eng, M.D., Ph.D., Chair, Genomic Medicine Institute; Robert Silverman, Ph.D., and Warren Heston, Ph.D., both of the Department of Cancer Biology; focused on whether the androgen receptor (AR) molecule offers evidence of the tumor suppressor protein PTEN. The research discovered that AR inhibits PTEN expression in prostate cancer cells, but stimulates it in breast cancer cells.
The conclusions, published in the Oct. 21, 2011 issue of Oncogene, explain why prostate cancer progression is associated with increased AR expression (and a common prostate cancer treatment strategy involves blocking AR), while most breast cancers occur post-menopause, after AR production has ceased (making AR supplementation a strategy for treating breast cancer).
Dr. Eng and her colleagues have mapped the interaction between AR and PTEN in both prostate and breast cancer cells, which suggests that this interaction activates or represses subsequent gene expression depending on organ-specific cofactors. Although PTEN is a known tumor suppressor, and loss of PTEN expression has been associated with numerous cancers (including breast and prostate cancers), its regulation has not been well understood. The current data provide new information regarding PTEN regulation, and suggest that identifying regulatory cofactors will be a valuable next step in determining cancer risk, as well as potential new therapies.
How are changes in the AR gene related to health conditions?
androgen insensitivity syndrome - caused by mutations in the AR gene
More than 600 different mutations in the AR gene have been identified in people with androgen insensitivity syndrome. Most of these mutations are changes in single DNA building blocks (base pairs). Other mutations insert or delete multiple base pairs in the gene or affect how the gene is processed into a protein. Some changes in the AR gene lead to an abnormally short version of the androgen receptor protein; others result in the production of an abnormal receptor that cannot bind to androgens or to DNA. As a result, cells that are sensitive to androgens become less responsive to these hormones or unable to use these hormones at all.
Mutations that completely eliminate the function of the androgen receptor cause complete androgen insensitivity syndrome. Genetic changes that significantly reduce but do not eliminate the receptor’s activity cause partial androgen insensitivity syndrome. Mild androgen insensitivity syndrome results from changes that only slightly reduce the activity of the receptor.
spinal and bulbar muscular atrophy - caused by mutations in the AR gene
Spinal and bulbar muscular atrophy results from an expansion of the CAG trinucleotide repeat in the AR gene. In people with this disorder, CAG is abnormally repeated from 38 to more than 60 times. Although the extended CAG region changes the structure of the androgen receptor, it is unclear how the altered protein disrupts nerve cells. Researchers believe that a fragment of the androgen receptor protein containing the CAG repeats accumulates within these cells and interferes with normal cell functions. This buildup leads to the gradual loss of nerve cells in the brain and spinal cord that control muscle movement.
androgenetic alopecia - associated with the AR gene
Alterations in the AR gene are associated with an increased risk of androgenetic alopecia (also known as male-pattern baldness in men and female-pattern baldness in women). The variations result from small changes in the number or types of DNA building blocks (base pairs) that make up the AR gene. These genetic changes appear to be most frequent in men with hair loss that begins at an early age. Researchers believe that AR gene variations may increase the activity of androgen receptors in the scalp. Although androgenetic alopecia is related to the effects of androgens on hair growth, it remains unclear how changes in the AR gene increase the risk of patterned hair loss in men and women with this condition.
breast cancer - associated with the AR gene
Researchers have considered a possible relationship between the length of the CAG repeat region in the AR gene and a woman’s chance of developing breast cancer. The results of research studies have been mixed. Some studies have suggested that a long CAG repeat region is associated with an increased risk of breast cancer in women, and that a shorter CAG repeat region is associated with a reduced risk. Other research indicates that a shorter CAG repeat region may be related to an increased risk of both breast cancer and noncancerous (benign) breast disease. Shorter CAG repeat regions have also been associated with more aggressive forms of breast cancer. Additional research is needed to clarify what role, if any, this region of the AR gene plays in determining breast cancer risk.
other cancers - associated with the AR gene
At least 85 mutations in the AR gene have been associated with prostate cancer. Almost all of these mutations are somatic, which means they develop during a person’s life and occur only in certain cells (in this case, cells in the prostate). Somatic mutations are not inherited and are not passed to future generations.
Some studies have shown an increased risk of prostate cancer in men with a short CAG repeat region in the AR gene; however, other studies did not find this connection. Researchers also believe that extra copies of the gene in cancer cells may be associated with the progression of prostate cancers.
Recent studies have also suggested that a longer CAG repeat region in the AR gene may increase the risk of endometrial cancer in women.
“We now see how androgen affects PTEN expression – and ultimately cancer,” said Dr. Eng. “Our observations help explain why this prostate cancer risk can be halved by drinking red wine, which increases PTEN expression. Our data also suggest that treatment of the exact same cancer must be personalized for males and for females.”
About Cleveland Clinic
Celebrating its 90th anniversary, Cleveland Clinic is a nonprofit multispecialty academic medical center that integrates clinical and hospital care with research and education. It was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based upon the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. About 2,800 full-time salaried physicians and researchers and 11,000 nurses represent 120 medical specialties and subspecialties. Cleveland Clinic Health System includes a main campus near downtown Cleveland, eight community hospitals and 16 Family Health Centers in Northeast Ohio, Cleveland Clinic Florida, the Lou Ruvo Center for Brain Health in Las Vegas, Cleveland Clinic Canada, and opening in 2013, Cleveland Clinic Abu Dhabi. In 2010, there were 4 million visits throughout the Cleveland Clinic health system and 155,000 hospital admissions. Patients came for treatment from every state and from more than 100 countries.
Contact: Dan Doron