WASHINGTON -- Adding a medication used to treat epilepsy, bipolar disorder and migraines to a blood pressure medicine reversed some aspects of breast cancer in the offspring of mice at high risk of the disease because of the high fat diet fed to their mothers during pregnancy. Conversely, this treatment combination increased breast cancer development in the offspring whose mothers had not been fed a high fat diet during pregnancy. The study by Georgetown Lombardi Comprehensive Cancer Center researchers appeared December 30, 2019, in Scientific Reports.
The key drug in the study regimen was valproic acid which, among several targets, inhibits histone deacetylase (HDAC), an important epigenetic silencer of genes. In contrast to mutations that permanently disrupt the normal functions of genes, epigenetic modifications are reversible. Valproic acid was combined with the blood pressure medication hydralazine that inhibits another critical epigenetic regulator, DNA methyltransferase (DNMT). Early treatment studies in people have shown that these two drugs can work in tandem to disrupt tumor growth.
"We believe that our research is the first to show that we can reverse some aspects of increased breast cancer risk found in offspring of mouse mothers fed a high fat diet during pregnancy," said Leena A. Hilakivi-Clarke, PhD, a professor of oncology at Georgetown Lombardi. "This finding may have important implications in people because exposures in the womb to certain chemicals, or a mother's high fat diet, or being obese, can subsequently increase a daughter's breast cancer risk."
These research findings demonstrate how impactful an epigenetic methyl group addition or subtraction from DNA can be. Compounds that reduce methylation of tumor suppressor genes that are excessively methylated (hypermethylated) can be beneficial. However, these drugs can have the opposite effect if tumor suppressor genes are not hypermethylated; they may remove methyl groups from cancer-causing genes, making these genes more active and potentially leading to more aggressive cancers.
The other key aspect of this finding involves the potential impact of diet on cancer risk. Many fruits and vegetables have compounds (such as flavones) that chemically react in the same ways as the HDAC- and DNMT-inhibiting drugs in this study. Some compounds in these foods, especially folic acid, have opposite effects. This research suggests that exposure to a high fat diet or endocrine disrupting chemicals in the womb might be reversed by the consumption of foods high in DNMT and HDAC inhibitors, while those who have not had such exposures might also gain a cancer protective benefit from consuming foods high in folic acid. The scientists note, however, that their findings, particularly as they relate to diet, need to be studied in people.
"Our next step will be to try to identify biomarkers in humans that indicate an exposure in the womb to diets or endocrine disrupting chemicals that could increase breast cancer risk later in life," said Hilakivi-Clarke. "If we can identify such biomarkers, we'll look to see if specific foods consumed by women can reverse epigenetic changes to their DNA that might lead to increased breast cancer risk."
In addition to Hilakivi-Clarke authors from Georgetown University include Fabia de Oliveira Andrade, Nguyen Nguyen, and Anni Warri. Warri also has an appointment with University of Turku Medical Faculty in Finland.
The authors report no disclosures relevant to this study.
This research was supported by a National Cancer Institute grants R01-CA164384 and P30-CA51008.
de Oliveira Andrade F, et al. Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy. Scientific Reports. 30 December 2019. DOI: 10.1038/s41598-019-56854-5.
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute (NCI) as a comprehensive cancer center. A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington D.C. area. It serves as the research engine for MedStar Health, Georgetown University's clinical partner. Georgetown Lombardi is also an NCI recognized consortium with John Theurer Cancer Center/Hackensack Meridian Health in Bergen County, New Jersey. The consortium reflects an integrated cancer research enterprise with scientists and physician-researchers from both locations. Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic, translational and clinical research, patient care, community education and outreach to service communities throughout the Washington region, while its consortium member John Theurer Cancer Center/Hackensack Meridian Health serves communities in northern New Jersey. Georgetown Lombardi is a member of the NCI Community Oncology Research Program (UG1CA239758). Georgetown Lombardi is supported in part by a National Cancer Institute Cancer Center Support Grant (P30CA051008). 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 health and science center with a four-part mission of research, teaching, service 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).