April 17, 2013--------News Archive

Excess estrogen in pregnancy can increase breast cancer risk in daughters

Two researchers at the National Institutes of Health discovered a new genetic link between the rapid growth of healthy fetuses and the uncontrolled cell division in cancer. The findings shed light on normal development and on the genetic underpinnings of common cancers.

The work, conducted using mouse and human tissue, appears in today’s issue of the Proceedings of the National Academy of Sciences. The authors, Julian C. Lui, Ph.D., and Jeffrey Baron, M.D., work at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

“We’ve long known that some of the genes that promote rapid growth in prenatal and early postnatal life become reactivated in cancer cells,” said Dr. Baron. “Now we’ve identified a molecular switch that appears to turn on some of these genes, taking us a step forward in understanding normal body growth and the abnormal growth in some types of cancer.”

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 breast cancer 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 molecular abnormalities that can contribute to breast cancer risk and risk of breast cancer recurrence, says Hilakivi-Clarke.

For the study, the researchers compared the gene DNA methylation 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 breast cancer patients who develop resistance to hormonal therapy and are at high risk of recurrence," Leena 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 breast cancer risk and prevent development of resistance to tamoxifen 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."

Leena Hilakivi-Clarke, Ph.D.
Professor of Oncology
Georgetown Lombardi

In addition to Hilakivi-Clarke and Clarke, authors include Riitta Luoto of the UKK Institute in Tampere, Finland; Xiao Zhang and Jason Xuan of Virginia Tech; and Nguyen Nguyen, Xiyuan Zhang, Jin Lu, and Alan Zwart of Georgetown Lombardi. U.S. funding for this research was provided by the National Cancer Institute (U54 1U54CA149147 and 1R01CA164384).

Funding was also provided by Pirkanmaa Hospital, Academy of Finland, and Ministry of Education and Culture of Finland. Hilakivi-Clarke reports having no personal financial interests related to the study. About Georgetown Lombardi Comprehensive Cancer Center Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future.

Georgetown Lombardi is one of only 41 comprehensive cancer centers in the nation, as designated by the National Cancer Institute (grant #P30 CA051008), and the only one in the Washington, DC area. For more information, go to http://lombardi.georgetown.edu.

About Georgetown University Medical Center Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC's mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis – or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute's website at http://www.nichd.nih.gov/.

About the National Institutes of Health (NIH):

NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Original article: http://explore.georgetown.edu/documents/70071/?PageTemplateID=141