BRCA1 gene inhibits estrogen and progesterone

It's been known that the breast cancer susceptibility gene BRCA1 regulates use of estrogen in breast and other cells, but now researchers at Georgetown University Medical Center have discovered that it also controls activity of a second sex steroid hormone, progesterone.

The findings, conducted in cell culture and in mice and reported by the researchers in the January issue of Molecular Endocrinology, could help explain why women who have mutations in their BRCA1 gene are susceptible to a number of different "hormone-dependent" cancers, including those of the breast, endometriun and cervix.

It also has implications for ordinary cancers that arise because a normal BRCA1 gene is under-expressed, said the study's principal investigator, Eliot Rosen, MD, PhD, professor of oncology, cell biology, and radiation medicine at the Lombardi Comprehensive Cancer Center.

For example, he says that up to 40 percent of breast tumors are deficient in BRCA1, "and it may be that some patients could benefit not only from an anti-estrogen therapy, like tamoxifen, but also from an anti-progesterone agent.

"We don't know if that is true yet, of course, but it is certainly worth investigating, given our findings," Rosen said.

The BRCA1 gene and a second gene, BRCA2, were discovered to be breast cancer susceptibility genes in 1994 and 1995, respectively. Women who inherit faulty copies of one of these genes have up to an 80 percent increased risk of developing breast cancer by age 70, and are also more likely to be diagnosed with ovarian cancer.

Rosen and his research team undertook the study to understand why loss of the BRCA1 gene results in cancers in tissues that are dependent on hormones. They focused on the progesterone hormone, in part, because of the observation that women who use hormone replacement therapy that includes both estrogen and progestin (a synthetic form of progesterone) are at greater risk of developing breast cancer than women who use only estrogen replacement.

The use of progesterone in the breast is tightly regulated and is primarily activated when growth in cells is needed, such as during the female menstrual cycle and to support a pregnancy. A cell's use of progesterone and other such hormones is controlled by specific receptor proteins, located inside cells, which bind on to the hormone. This process activates the receptor, which then migrates to the cell nucleus to stimulate gene expression.

To find out what role BRCA1 played in progesterone receptor signaling, the Lombardi research team conducted a series of experiments. In one set of cell culture studies in the laboratory, they used breast cancer cells that were responsive to progesterone, and then genetically manipulated them to either over or under-express the BRCA1 gene in order to assess the gene's effect on progesterone receptor signaling.

They also used mice in which the BRCA1 gene was partially deleted, but only in breast tissue. The animals were treated with estrogen, or progesterone, or both, and response of the mammary gland was compared with that of normal mice.

In this way, the researchers concluded that BRCA1 interacts physically with the progesterone receptor, and stops it from activating other genes. It does this even in the absence of the progesterone hormone, and, thus, acts as a strong check on errant growth.

"But in mice deficient in BRCA1, we found that estrogen plus progesterone has a particularly large effect in stimulating the growth of mammary epithelial cells − an effect much greater than the effects of either hormone used alone," Rosen said.