Inhibiting progesterone may prevent breast cancer in women with a certain genetic predisposition to the disease, according to the results of a new study in mice that could lead to the development of a new drug for breast cancer prophylaxis.

Women carrying a mutation in the tumor suppressor gene BRCA1 are up to seven times more likely to develop breast cancer than women without the mutation. Mutated BRCA1, most common in women of Ashkenazi Jewish background, also increases the risk of ovarian and other cancers, although the mechanism of BRCA1-mediated cancer development is unclear.

Women with a family history of breast or ovarian cancer can undergo genetic testing, but, at present, carriers of mutated BRCA1 have two less-than-ideal choices: rely on constant monitoring to try to detect the cancer at an early and curable stage, or opt for breast and ovary removal to eliminate the possibility of developing cancer in the first place. For many at-risk women, a pharmacological intervention would be a welcome alternative.

Previous epidemiological and laboratory research has suggested that progesterone has a role in driving breast cancer development. Hormone replacement therapy with estrogen and progesterone, but not estrogen alone, increases the risk of breast cancer in postmenopausal women. In addition, in cell culture, the BRCA1 protein has been shown to inhibit the action of the progesterone receptor.

In the 1 December 2006 issue of Science, Eva Lee and her colleagues at the University of California, Irvine describe work in mice that may lay the groundwork for pharmacological prevention of breast cancer. Lee's team studied nullparous mice with mutant BRCA1 and p53 (another tumor suppressor gene that is commonly mutated in breast cancer patients). These mice had the increased growth and branching of mammary tissue normally seen during pregnancy. Moreover, all of the double-mutant mice developed breast cancer by eight months of age. On the other hand, mice treated with mifepristone (RU 486), a progesterone inhibitor that is used in humans to induce abortion, remained cancer-free at 12 months of age. Mammary cells from the double-mutant mice expressed more progesterone receptors than those from controls or p53-mutant mice

Mouse and human mammary cell cultures showed that functional BRCA1 protein is required for the timely breakdown of the progesterone receptor. Inactivated BRCA1 leads to the presence of more progesterone receptors, which in turn leads to more progesterone-mediated cell proliferation, increasing the chance that a cancer-promoting mutation will occur during cell division.

Although mifepristone seemed to work wonders in mice, the fact that it acts on several hormone receptors may mean that it is not be appropriate for long-term use. Lee tells Lab Animal that her team is currently working to identify more-specific progesterone blockers.