Breast cancer risk traced back to the womb.

Prenatal exposure to high concentrations of the sex hormone estrogen may foretell a woman's future breast cancer risk, according to research by a team of U.S. and Swedish investigators.

Epidemiologist Dimitrios Trichopoulos of the Harvard School of Public Health in Boston first proposed the link in 1990. Now, he and his Swedish colleagues have collected the first empirical evidence to support that theory.

"The most dramatic finding is that events so early in life may program the female breast with regard to a future cancer risk," says co-worker Hans-Olov Adami of the Uppsala University Hospital in Uppsala, Sweden.

The team began by studying the birth records of 458 women who had develped breast cancer and a control group of 1,197 women who had not. All the women had been delivered at Uppsala University Hospital, where midwives have routinely recorded extensive maternity and delivery information since 1874.

To estimate fetal exposure to estrogen, the researchers looked for babies with a birth weight of eight pounds or more. Scientists believe that heftier infants are more likely to have been exposed to high concentrations of growth-promoting maternal estrogen. Analysis revealed that study participants who weighed eight pounds or more at birth were 30 percent more likely to develop breast cancer than participants who weighed less at birth.

That finding, reported in the Oct. 24 LANCET, hints at estrogen's role in promoting breast cancer but is not sufficient to establish a clear link between birth weight and a future cancer risk. Researchers must conduct a much larger study to rule out the possibility that birth weight and the risk of breast cancer are associated by chance, Adami cautions.

Next, the team homed in on cases of maternal toxemia, a pregnancy-induced hypertension associated with low concentrations of estrogen. They discovered that daughters of women who had experienced toxemia during pregnancy were 75 percent less likely to develop breast cancer than daughters of women who did not have toxemia. That statistically significant finding raises the possibility that the lower estrogen concentrations associated with toxemia conferred a cancer protection on the breast cells of the fetus, Adami says.

Some scientists believe that chronic exposure to estrogen may cause breast cells to proliferate, thus increasing the risk that cancer will develop (see p.298). However, the new study provides the first hint that estrogen may influence the breast cells of the fetus, perhaps priming those cells to develop cancer years later, Trichopoulos notes.

Still, the new study doesn't prove the link between prenatal exposure to estrogen and future breast cancer risk, Adami cautions. For example, toxemia remains a complex and poorly understood condition. Some other factor associated with toxemia -- but not with low estrogen concentrations -- may give the female fetus an edge against breast cancer, Adami says. Both Adami and Trichopoulos say additional research is needed to confirm their findings.