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USC Team Identifies Mutations Linked To Breast Cancer Risk During HRT Tx

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Researchers from the Keck School of Medicine of the University of Southern California have identified a genetic mutation that might increase the likelihood that certain women undergoing hormone replacement therapy might develop breast cancer.

These findings, if validated, may lead to a molecular diagnostic that could help physicians better determine which women to treat with HRT.

“We already know that only some women who use hormone replacement therapy with estrogen and progestin go on to develop breast cancer,” said Giske Ursin, associate professor of preventive medicine at the Keck School, and a study co-author. “If we could have a way of picking out the subset of women who are at risk for breast cancer from using standard hormone replacement therapy, we could offer these women some other treatment for their postmenopausal complaints.”

Studying mammograms from more than 200 women, the Keck School researchers found that women with a mutation developed denser breast tissue than women without the variant after using estrogen and progestin therapy.

In their study, the researchers wanted to learn which polymorphisms might link female hormones to increased breast density. They obtained mammograms and DNA from 233 postmenopausal women ages 45-75 randomly assigned to take either estrogen-and-progestin therapy, estrogen-only therapy, or a placebo.

The scientists scanned each participant’s DNA for the presence of five genetic polymorphisms associated with the body’s ability to break down estrogen or progesterone: for estrogen metabolism, COMT(Val158Met), CYP1B1(V432L), UGT1A(

When the researchers took women’s mammograms 12 months into the trial and compared them to mammograms taken at baseline, they found that women on estrogen-and-progestin therapy and with either one or two copies of the AKR1C4 polymorphism had a “substantially greater” increase in breast density than women who had no copies of that polymorphism.

Among study participants as a whole, those on estrogen-and-progestin therapy saw their breast tissue grow 7 percent denser, while those taking estrogen alone had “somewhat less” of an increase in breast density. Women on placebo had no increase in breast density.

“We do not yet know whether an increase in breast density translates into an increase in breast cancer risk,” the researchers said. “However, breast density may be a measure of breast cell multiplication,” suggesting that the more breast cells multiply over a lifetime, the greater the breast cancer risk.

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