Cancer link: gene regulates progesterone effect on breast cells.

Since its discovery in 1994, the BRCA1 gene has given up its secrets grudgingly. Early on, scientists recognized that it kept cancer at bay. Women carrying a mutation in the gene face an extremely high risk of breast and ovarian cancer. Researchers have struggled to understand how the protein encoded by a normal BRCA1 gene works.

A study in mice now suggests one possibility: The BRCA1 protein moderates the hormone progesterone's effect in breast cells. The protein appears to calm those cells when progesterone urges them to divide and grow.

Earlier research had shown that BRCA1 protein orchestrates the repair of damaged DNA. But since that process occurs continuously in every cell throughout the body, the finding failed to explain how a mutated BRCA1 would predispose a woman specifically to cancers of the breasts or ovaries.

In the new study, the researchers genetically engineered mice so that they didn't make BRCA1 protein. Breast tissue in these animals grew abnormally, creating many branching mammary ducts of a type usually seen only in pregnant mice, says Eva Y.-H.P. Lee, a molecular biologist at the University of California, Irvine.

Compared with normal breast cells, the breast cells in the genetically altered mice were also three times as likely to have progesterone receptors--proteins on the cell surface that serve as docks for the hormone. When progesterone binds to the receptor, it sends a signal that's transferred to the cell nucleus. Progesterone typically instructs a cell to proliferate.

Normally, after a progesterone receptor transmits a growth signal, the cell destroys the receptor, Lee says. However, animals lacking BRCA1 failed to complete this routine cleanup process, she and her colleagues report in the Dec. 1 Science. In some cases, other progesterone molecules bind to the already used receptor, generating more proliferation signals.

All the mice in a group bereft of BRCA1 protein developed tumors within 5 to 9 months, the researchers found. But when similar mice received the antiprogesterone drug mifepristone, they showed no cancer during the 12 months of observation.

The study "places the progesterone receptor right in the middle of the physiology" of BRCA1-related breast cancers, says physician Steven Narod of the University of Toronto.

"This provides compelling evidence that abnormal branching [in mammary glands] is due to aberrant progesterone signaling" says oncologist Nicholas Turner of the Breakthrough Breast Cancer Research Centre in London.

However, Narod notes that mice aren't a perfect model for the human disease because healthy women with BRCA1 mutations don't exhibit the abnormal duct branching seen in the animals in this study.

Antiprogesterone drugs might control abnormal signaling, thereby preventing or treating cancers in some women with the BRCA1 mutation, says oncologist Eliot M. Rosen of Georgetown University in Washington, D.C. At present, "the most effective protection [against breast cancer for women with a BRCA1 mutation] is drastic surgery to remove the ovaries and both breasts," he says. An antiprogesterone "might be a non-surgical approach," he adds.

Narod cautions that determining the preventive effects of an antiprogesterone drug would require a massive clinical trial of healthy women. A test of an antiprogesterone as a treatment for breast cancer might come first, he says.