Feeding pregnant female mice a diet high in fat derived from common corn oil resulted in genetic changes that substantially increased breast cancer susceptibility in three generations of female offspring, reports a team of researchers led by scientists at Georgetown Lombardi Comprehensive Cancer Center.

Their study, published online today in Breast Cancer Research, suggests a research direction for examining the diet of pregnant women, says the study's senior author, Leena Hilakivi-Clarke, PhD, professor of oncology at Georgetown Lombardi.

"It is believed that environmental and life-style factors, such as diet, plays a critical role in increasing human breast cancer risk, and so we use animal models to reveal the biological mechanisms responsible for the increase in risk in women and their female progeny," says Hilakivi-Clarke.

A high-fat diet is linked to excess inflammation, and a number of epidemiological studies have made the connection between inflammation and risk of cancer, she says.

Hilakivi-Clarke has found in earlier studies that mice that eat a high fat diet when they are pregnant have "daughters" that are at excess risk of the cancer. This study, however, found that if pregnant mice were switched to a high fat diet during their second trimester when the germ line mediating genetic information from one generation to another forms in the fetus, an increase in breast cancer risk is also seen in "great granddaughters.

A gene screen revealed a number of genetic changes in the first (daughter) and third (great granddaughter) high-fat mice generations, including several genes linked in women to increased breast cancer risk, increased resistance to cancer treatment, poor cancer prognosis and impaired anti-cancer immunity. The researchers also found three times as many genetic changes in third generation than first generation mammary tissue between high-fat diet progeny and the control group's offspring.

"The soil in the breast, so to speak, remained fertile for breast cancer development in our high-fat experimental mice," Hilakivi-Clarke says.

The amount of fat fed to the experimental mice matched what a human might eat daily, says Hilakivi-Clarke. In the study, both the control mice and the mice fed chow with high levels of corn oil ate the same amount of calories and they weighed the same. "But our experimental mice got 40 percent of their energy from fat, and the control mice got a normal diet that provided 18 percent of their energy from fat," she says. "The typical human diet now consists of 33 percent fat."

Pregnant mice in the experimental arm ate the high-fat diet starting at gestation day 10, the time when a daughter's ovarian eggs (and so their germ cells) begin to develop. This corresponds roughly to a woman's second trimester. By comparison, eating a high-fat diet before and during pregnancy increase breast cancer risk in the subsequent two generations, but does not cause inheritable changes in the germ cells, Hilakivi-Clarke says.

"Studies have shown that pregnant women consume more fats than non-pregnant women, and the increase takes place between the first and second trimester," she says.

"Of the 1.7 million new cases of breast cancer diagnosed in 2012, 90 percent have no known causes," she says. "Putting these facts, and our finding, together really does give food for thought."

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Study co-authors from Georgetown Lombardi include graduate student Nguyen M. Nguyen, Fabia de Oliveira Andrade, PhD, Lu Jin, MS, Xiyuan Zhang, MS, Madisa Macon, PhD, M. Idalia Cruz, Carlos Benitez, and Sonia de Assis, PhD. Bryan Wahrenberg, from the University of Texas MD Anderson Cancer Center, and Xiao Wang, MS, and Jianhua Xuan, PhD, from Virginia Tech also collaborated in the research.

The authors report having no personal financial interests related to the study.

The study was supported by National Institutes of Health awards U54-CA149147, R01-CA164384, and P30-CA51008.

About Georgetown Lombardi Comprehensive Cancer Center

Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute as a comprehensive cancer center -- the only cancer center of its kind in the Washington, DC area. A part of Georgetown University Medical Center and MedStar Georgetown University Hospital, Georgetown Lombardi 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. Connect with Georgetown Lombardi on Facebook (Facebook.com/GeorgetownLombardi) and Twitter (@LombardiCancer).

About Georgetown University Medical Center

Georgetown University Medical Center (GUMC) 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, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award from the National Institutes of Health. Connect with GUMC on Facebook (Facebook.com/GUMCUpdate), Twitter (@gumedcenter) and Instagram (@gumedcenter).