Excess estrogen during pregnancy could inhibit BRCA1 in offspring

An excess of estrogen during pregnancy can inhibit BRCA1 in female offspring, thus increasing their risk for breast cancer. Data on these findings were presented at the American Association for Cancer Research Annual Meeting in Washington, D.C.

According to researchers, BRCA1 silencing by methylation in utero could be an important mechanism that increases the risk for breast cancer later in life. However, there could be a way to lower the risk before the cancer develops, according to researchers.

“We may be able to identify women at increased risk of developing breast cancer by looking for BRCA1 that has been methylated as a marker of having been exposed to excess estrogen levels in utero,” researcher LeenaHilakivi-Clarke, PhD, a professor of oncology at Georgetown Lombardi, said in a press release.

They investigated in utero estradiol levels from weeks 8 through 12 and 26 through 28, and buccal swab DNA was taken from 22 of the women’s daughters at age 1. The researchers then compared the gene DNA methylation profiles of the daughters to databases collected from a large number of breast cancer patients in the Cancer Genome Atlas (TCGA).

According to the abstract, 223 genes displayed significantly higher and 666 genes displayed significantly lower DNA methylation patterns in the top estradiol quintile daughters, compared with the bottom estradiol daughters.

Of the hypermethylated genes in the buccal swab DNA, researchers found that 23% were more methylated in tumors compared with normal mammary tissues in data from women in the TCGA. Similarly, of the hypomethylated genes in buccal swab DNA, 25% were hypomethylated in the tumors in TCGA.

Data indicate the most active hypermethylated gene in the high in utero estradiol exposed daughters was BRCA1 (3.7-fold; P<.006), and this gene was also methylated in TCGA tumors.

Additionally, they found several members of the unfolded protein response (UPR) pathway, among the hypomethylated genes, including EIF2AK3 (P<.007), IKBKB (P<.01) and NFkB (P<.05).

“Given these findings, perhaps we can identify those breast cancer patients who develop resistance to hormonal therapy and are at high risk of recurrence,” Hilakivi-Clarke said. “Because several drugs are now available to reverse an increase in gene methylation, it may be possible to reverse the increase in breast cancer risk and prevent development of resistance to tamoxifen in these women.”

In addition to BRCA1, another gene abnormality was found in the unfolded protein response (UPR) pathway, which has been linked to risk for breast cancer and tamoxifen resistance.

Furthermore, researchers confirmed that the same UPR genes were also hypomethylated in breast cancers in women, compared with normal breast tissue (just as breast cancer cells that are resistant to tamoxifen treatment, compared with tamoxifen sensitive breast cancer cells), researchers wrote.

“It does not matter how BRCA1 is eliminated – by mutation or epigenetic silencing – the end result is the same: there is less BRCA1 to defend the cells from becoming cancerous,” Hilakivi-Clarke said.

For more information:

Hilakivi-Clarke LA. Abstract #3638. Presented at: the American Association for Cancer Research Annual Meeting 2013; April 6-10, 2013; Washington, D.C.

Disclosure: The study was funded by the National Cancer Institute, Pirkanmaa Hospital, Academy of Finland, and Ministry of Education and Culture of Finland. Hilakivi-Clarke reports no relevant financial disclosures.