Researchers are focusing on the good side of the BRCA1 gene-notorious as a cancer-causing gene-in its normal role of preventing or controlling breast cancer.
The BRCA1 gene, when found in its mutated form, gives a woman as much as an eight-fold increase in her risk of developing breast cancer. Additionally, she has as much as a 10-fold increase in her risk of developing ovarian cancer.
But BRCA1's notoriety is based entirely on its tendency to malfunction and cause cancer. In reality, though, BRCA1 is behind only about 10 percent of breast cancer cases. In the other 90 percent of women who develop breast cancer-and in almost all of the women who never develop the disease-the gene is completely normal. And yet, the role BRCA1 (the first of the two BRCA genes to be discovered) may play in keeping breasts healthy-rather than making them sick-has been more or less ignored.
Until now.
Thanks to a $600,000, three-year grant from the California Breast Cancer Research Program, Donna Williams-Hill, Ph.D., the principal investigator and assistant professor of radiation oncology, Colin Hill, Ph.D., co-principal investigator and associate professor of radiation oncology, and their collaborators are focusing on just what BRCA1 does in the human body, and how they might exploit or enlist this gene in its normal state to prevent or control breast cancer.
According to Williams-Hill, a normal BRCA1 gene helps to keep cells on the straight and narrow. It is suppose to stop cells from proliferating out of control and help them repair damaged bits of their DNA. It is also supposed to stop cancerous tumors from ever getting started.
And it does its job particularly well. Previous USC studies on rats have shown that the higher the level of expression of the BRCA1 gene, the more quickly and easily DNA damage is repaired-thus reducing the likelihood that the cell will become cancerous. That is why Williams-Hill believes her research is going to show that the more active normal BRCA1 is in a woman's cells throughout her life, the better that woman will be at repairing DNA damage and the lower her breast cancer risk will be.
Williams-Hill also believes that the month-to-month, year-to-year changes in a woman's hormonal status play into her breast cancer risk as well. It seems that BRCA1 expression goes up and down with the amount of estrogen a woman is producing-and how quickly her cells are dividing. "It makes sense in a mammary cell that during the proliferative stage it would make more tumor suppressor," she says. "It may be that women who don't make enough of the hormone would be more at risk during that time."
And if that is true, she points out, then protecting a woman against breast cancer may well be a matter of making sure she is getting enough BRCA1 activity throughout her life-or during certain vulnerable phases of it.
That is why the various research projects of Williams-Hill and her USC colleagues will look at what happens to BRCA1 as estrogen levels rise and fall. Hill will look at how female rats in different stages of their estrogen cycle respond to irradiation of their mammary cells, which would normally cause DNA damage to the cells. Giske Ursin, M.D., Ph.D., assistant professor of preventive medicine, will share her extensive collection of tissue samples from women with breast cancer. These samples are particularly useful, says Williams-Hill, because they contain information on the hormonal status of the woman at the time of her disease's inception such as her age, whether she was pre- or post-menopausal, whether she had used oral contraceptives or was using hormone replacement therapy. And along with Roger Duncan, Ph.D., associate professor of molecular pharmacology and toxicology, Williams-Hill will work on ways to measure the level of BRCA1 gene expression in these rat and human tissues by measuring the gene's protein product.
"Some people just naturally make more BRCA1 than others," notes Williams-Hill. "One of the things we're trying to determine is, are people who make less BRCA1 more at risk for breast cancer? We think they may well be."