Male sex hormones cooperate with breast cancer gene to suppress tumors

June 27, 2003

BRCA-2, a gene linked with breast and ovarian cancer, cooperates with male sex hormones to enhance its ability to activate transcription of genes, which may suppress tumor formation in normal cells, Salk Institute researchers have found.

The study, published in the June 10 Proceedings of the National Academy of Sciences, provides details on how the normal form of the gene may work, and how mutant forms of BRCA-2 may malfunction and therefore likely contribute to the development of breast cancer. It also gives greater insight into the causes of male breast cancer. BRCA-2 is one of two genes (the other is BRCA-1) linked to at least 10 percent of all breast cancers; the mutant form appears in nearly all male breast cancers.

Sook Shin, a postdoctoral fellow at the Salk, and Inder Verma, a Salk professor of genetics, found that the normal form of BRCA-2 enhanced the activity of androgen receptors that bind to androgens, which are male sex hormones like testosterone. Androgens exhibit antiproliferative activity in addition to their actions in developing male sex characteristics. Women also produce androgens, but have different levels in their bodies; the hormones play a role in female and male cancers.

In its mutated form, however, BRCA-2 could not enhance the androgen receptor's activity and thus may allow cancer cells to proliferate, the scientists discovered. Interestingly, for BRCA2 to function, it needs to synergize with co-activators located on the cell nucleus named GRIP1, a protein previously identified by Salk scientists working on nuclear hormone receptors in Salk Professor Ron Evans' laboratory.

"We think that BRCA-2 may be involved in DNA repair, or synthesis of new gene products, but haven't had enough detail on how this gene functions," said Verma. "This study shows how BRCA-2 helps androgen receptors do a better job of perhaps suppressing tumors, and may help us arrive at new targets for treating or preventing breast cancer."

By comparing mutated and normal forms of BRCA-2 in mouse cells, Sook Shin found that the normal BRCA-2 enhanced the androgen receptors' transcriptional activity (copying DNA into RNA, ultimately producing gene products) by binding with the receptor. The binding, however, could only happen with the help of GRIP1 and enhanced activity by 10-fold. Furthermore BRCA2 and GRIP1 cooperate with histone acetyl transferase enzymes required for remodeling chromatin, the material in chromosomes, providing more evidence of BRCA-2's role in DNA repair and possible tumor suppression. The mutant form of BRCA-2 could not enhance androgen receptor activity.

The scientists' work will take several years before there is any sign of a new treatment for cancer. But since people who have the mutated form of BRCA-1 or 2 face a much higher chance of getting cancer than normal, knowing how these genes work should eventually prove invaluable in reducing cases of cancer.

Verma's team now is looking at what other genes are turned on by this interaction of BRCA-2, GRIP1 and male sex hormones, and what are the specific targets in the cell of the breast cancer genes.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.

Salk Institute

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