Drug Combination May Epigenetically Help Prevent Breast Cancer

Approximately one out of every eight women in the United States will develop breast cancer at some point in their lives. Breast cancer is considered to be the most lethal cancer for women outside of lung cancer. The economic implications of breast cancer are also huge; setting aside the medical costs faced, breast cancer costs a whopping $6.2 billion in lost wages.

With no surefire way to universally detect breast cancer early, it can be difficult to intervene early. Treatments must be known to work fast, and any risk factors that can be identified become powerful opportunities to help. Given the wide age range of women affected by breast cancer, side effects must be minimized wherever possible.

A cancer research team based out of Washington, D.C. recently published findings that a combination of existing drugs may reverse breast cancer development in mice whose mothers consumed high-fat diets during their pregnancy.  Contrastingly, they also found that the same combination of drugs can promote breast cancer growth in mice whose mothers were fed a healthy diet.

The team found that the genetic sequence of the mice was not altered in any way, so they turned to epigenetics to find the answer to this puzzling discovery.

How does this treatment work?

Both drugs of focus in this study can help regulate gene expression, but each drug separately affects a different epigenetic mechanism. Valproic acid is a medicine used to treat migraines, seizures and bipolar disorder. It is an inhibitor of an epigenetic modification called histone deacetylase (HDAC), which remove acetyl groups from core histones. Hydralazine is a popular blood pressure medication, which inhibits DNA methyltransferase (DMNT), the mechanism responsible for adding methyl groups to DNA.

The team found that the mice with mothers who consumed high-fat diets during pregnancy appeared to have hypermethylated—or silenced tumor suppressor genes, leaving them vulnerable to developing breast cancer.

These mice were administered the combination of valproic acid and hydralazine, which reduced the silencing of the tumor suppressor genes, allowing them to disrupt tumor growth as normal.

But some care must be taken with how these drugs are used. When mothers did not consume high-fat diets during pregnancy, mice did not have hypermethylated genes. In those mice, the administration of valproic acid with hydralazine actually demethylated tumor-causing genes, reversing their inhibition and rendering them active instead.

Future directions for these findings

Author and research lead Leena A. Hilakivi-Clarke, PhD, a professor of oncology at Georgetown Lombardi Comprehensive Cancer Center, is thrilled about the research and its implications for the future. “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. 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.”

First and foremost, the study must be repeated by other groups as well as validated within humans; but the results are promising nonetheless. Dr. Hilakivi-Clarke continued on to note, “Our next step will be to try to identify biomarkers in humans that indicate exposure in the womb to diets or endocrine-disrupting chemicals that could increase breast cancer risk later in life. 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.”

The positive effects of valproic acid combined with hydralazine need not come from synthetic medicines. Much produce has the HDAC and DMNT inhibitors utilized in this study; in patients who may have been exposed to poor maternal diet or endocrine-disrupting chemicals while in the womb, these foods might be particularly recommended to help protect against breast cancer.

In individuals without such womb exposure, folic acid may prove particularly protective. Either way, another useful research effort would involve identifying reliable biomarkers so that individuals’ exposure to these factors in the womb may be detected, and the appropriate dietary recommendations could be made accordingly.

Source:

Andrade, F.d.O., Nguyen, N.M., Warri, A. et al. (2019). Reversal of increased mammary tumorigenesis by valproic acid and hydralazine in offspring of dams fed high fat diet during pregnancy Sci Rep 9

Reference:

Karen Teber  “Neurologic Drug Combined with Blood Pressure Medicine Reduces Breast Tumor Development in Mice” GLCCC Research News, 30 Dec. 2019