Excess estrogen in pregnancy can silence BRCA1 in daughters, increasing breast cancer risk

April 9, 2013, Georgetown University Medical Center

Excess estrogen levels during pregnancy can disable, in their daughters, a powerful breast cancer tumor suppressor gene, say researchers at Georgetown Lombardi Comprehensive Cancer Center. They found the DNA repair gene BRCA1 to be silenced in one year-old girls exposed to a high hormonal fetal environment.

The researchers say their study, presented at the AACR Annual Meeting 2013, suggests that BRCA1 silencing by methylation in utero may be an important mechanism that increases risk later in life. And they say that, if confirmed, there could be ways of lowering that risk before breast cancer develops.

"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," says the study's lead author, Leena Hilakivi-Clarke, PhD, a professor of oncology at Georgetown Lombardi.

Not only was BRCA1 silenced by methylation in the one-year-old girls who developed in a highly estrogenic fetal environment, there were other that can contribute to breast cancer risk and risk of , says Hilakivi-Clarke.

For the study, the researchers compared the gene profiles of the daughters to publicly available databases collected from a large number of breast cancer patients in the Cancer Genome Atlas (TCGA). They found that those genes with altered methylation in the daughters of women with the highest pregnancy estradiol levels are also differentially methylated in breast cancer patients.

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

Researchers at Virginia Tech, who collaborated with Hilakivi-Clarke on this study, found that the UPR pathway was "hypomethylated" (genes were turned on or highly active), in the one-year old daughters. They further confirmed that the same UPR genes also were hypomethylated in breast cancers in women, compared to normal breast tissue, as well as in breast cancer cells that are resistant to tamoxifen treatment, compared to tamoxifen sensitive breast cancer cells.

"When these UPR genes are activated it means that damaged cells that should die do not, increasing the risk that cancer develops, and that cancer cells do not respond to treatment," says study collaborator, Robert Clarke, DSc, dean for research at Georgetown University Medical Center.

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

"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," she says.

Explore further: Breast cancer risks acquired in pregnancy may pass to next three generations

Related Stories

Breast cancer risks acquired in pregnancy may pass to next three generations

September 11, 2012
Chemicals or foods that raise estrogen levels during pregnancy may increase cancer risk in daughters, granddaughters, and even great-granddaughters, according to scientists from Virginia Tech and Georgetown University.

Study links breast cancer resistance with timing of soy consumption

April 2, 2012
Studies exploring the relationship between soy consumption and breast cancer have been mixed, but new research introduces a new thought: Could women with breast cancer who began eating soy as an adult develop a tumor more ...

Resistance to anti-estrogen therapy in breast cancer due to natural cell response

April 4, 2011
Most breast cancers are fueled by estrogen, and anti-estrogenic agents often work for a time to control the cancers. But many of these cancers become resistant to the drugs for reasons that are not understood, leaving patients ...

Recommended for you

Scientists block the siren call of two aggressive cancers

January 23, 2018
Aggressive cancers like glioblastoma and metastatic breast cancer have in common a siren call that beckons the bone marrow to send along whatever the tumors need to survive and thrive.

Boosting cancer therapy with cross-dressed immune cells

January 22, 2018
Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. The study is published in Nature Methods.

Workouts may boost life span after breast cancer

January 22, 2018
(HealthDay)—Longer survival after breast cancer may be as simple as staying fit, new research shows.

Cancer patients who tell their life story find more peace, less depression

January 22, 2018
Fifteen years ago, University of Wisconsin–Madison researcher Meg Wise began interviewing cancer patients nearing the end of life about how they were living with their diagnosis. She was surprised to find that many asked ...

Single blood test screens for eight cancer types

January 18, 2018
Johns Hopkins Kimmel Cancer Center researchers developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer.

Researchers find a way to 'starve' cancer

January 18, 2018
Researchers at Vanderbilt University Medical Center (VUMC) have demonstrated for the first time that it is possible to starve a tumor and stop its growth with a newly discovered small compound that blocks uptake of the vital ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.