Genetic clues may show which women face breast cancer risk from HRT

September 12, 2003

A genetic clue may eventually help physicians identify certain women who would face an increased risk of breast cancer from using hormone replacement therapy, according to researchers from the Keck School of Medicine of the University of Southern California.

Keck School scientists obtained mammograms on more than 200 women and found that those with a genetic variant developed denser breast tissue after using estrogen and progestin therapy than women without the variant.

Mammographic density is a risk factor for breast cancer and has been proposed as a marker for breast cancer risk.

"Our research is promising. We already know that only some women who use hormone replacement therapy with estrogen and progestin go on to develop breast cancer," says Giske Ursin, M.D., Ph.D., associate professor of preventive medicine at the Keck School and one of the study authors. "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."

The researchers presented their findings at a meeting called "SNPs, Haplotype, and Cancer: Application in Molecular Epidemiology," sponsored by the American Association for Cancer Research. SNPs is scientific shorthand for single nucleotide polymorphisms, which refer to differences in specific genes within the human genome.

Researchers explain that 99.9 percent of the genome is identical in all humans. But the rest of the genome is where it gets interesting--and where SNPs can be found. These polymorphisms are bits of the genetic blueprint that exist in different varieties within the population. They may account for characteristics as obvious as hair color or as complicated as the body's ability to break down hormones.

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

Scientists checked each participant's DNA for the presence of five genetic polymorphisms associated with progesterone action or the body's ability to break down estrogen or progesterone. Because of the way genes are inherited from both parents, each participant could either have two copies of the polymorphism, one copy or no copies.

When researchers took women's mammograms after 12 months on the trial and compared them to mammograms taken at baseline, they saw something striking. They found that among women on estrogen-and-progestin therapy, those with either one or two copies of a polymorphism in one of the genes that break down progesterone had a substantially greater increase in breast density than women who had no copies of that polymorphism.

The bodies of women with this genetic variant may not be able to break down progesterone as well as those without the polymorphism, researchers theorize. They did not see the same effects in women using estrogen-alone therapy.

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. However, breast density may be a measure of breast cell multiplication. Researchers believe the more breast cells multiply over a lifetime, the greater the breast cancer risk. The estrogen and progesterone naturally present in young women cause breast cells to multiply, but as a woman enters menopause, hormone levels plummet and breast cell multiplication slows.

Hormone replacement therapy in postmenopausal women introduces hormones present in very small amounts in such women. That means additional breast cell multiplication--and potentially greater breast cancer risk.
Additional Contacts:
John Weiner

American Association for Cancer Research

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