In Utero Exposure to Ethinyl Estradiol Linked to Tamoxifen Resistance and Breast Cancer Recurrence Interview with:

Leena Hilakivi-Clarke, PhD Professor of Oncology Georgetown University Washington, DC 20057

Dr. Leena Hilakivi-Clarke

Leena Hilakivi-Clarke, PhD
Professor of Oncology
Georgetown University
Washington, DC 20057 What is the background for this study?

Response: About 70% of women who develop breast cancer express estrogen receptors in their cancer. These patients are treated with endocrine therapies that target estrogen receptors. Endocrine therapies are effective in half of the patients, but the other half are resistant to the treatment and recur. Prior to the start of endocrine therapy, there is no way to predict who will respond to it and who will have recurrence of breast cancer. Therefore, it is not known which patients might benefit from an additional therapy to prevent recurrence, and what that additional therapy would entail. We wondered if resistance to endocrine therapy (we used tamoxifen) is pre-programmed by maternal exposure to the estrogenic endocrine disrupting chemical ethinyl estradiol (EE2). Previously, we and others have found that EE2 and other estrogenic compounds, when given during pregnancy, increase breast cancer risk in the female offspring in animal studies and among humans. The current study was done using a preclinical animal model that was used 50 years ago to discover that tamoxifen is an effective endocrine therapy for estrogen receptor positive breast cancer patients. What are the main findings?

Response: The main finding of the study was that in utero exposure to ethinyl estradiol increased de novo resistance (tumor never responded) to tamoxifen by 42% and acquired resistance (tumor recurred) by 83%. We also found that both de novo and acquired tamoxifen resistance in the in utero EE2 exposed animals could be prevented by adding valproic acid and hydralazine as a 2nd line therapy to tamoxifen. These two epigenetic modulating drugs normalized expression of four differentially expressed genes we identified in the mammary tumors of EE2 offspring and in endocrine therapy resistant human breast cancer cells. What should readers take away from your report?

Response: Caution should always be employed when findings obtained using animal models are translated to humans. That said, our results suggest that some breast cancers may be pre-programmed to be resistant to endocrine therapies because a patient was exposed to high levels of estrogenic endocrine disrupting chemicals in the womb. This pre-programming in the animal model was epigenetically mediated and involved changes in gene signaling patterns through reversible increase in DNA methylation. The in utero estrogen exposed patients, but not patients who have not been exposed to elevated in utero estrogenic environment, may benefit from adding histone deacetylase and DNA methyltransferase inhibiting drugs to endocrine therapy to prevent development of resistance to the treatment. What recommendations do you have for future research as a result of this study?

Response: Very few breast cancer patients know that they were exposed to an elevated in utero estrogenic environment, such as patients born to mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy. However, most patients have no idea whether they were exposed or not. It is therefore critical to identify markers in the breast tumors that will reveal if the breast cancer patient was exposed to estrogenic compounds in utero and consequently may show impaired response to endocrine therapy. In our study, we propose four marker genes indicative of maternal exposure to EE2 during pregnancy: ETV4, KLF4, LGALS3 and MICB. These four genes are either involved in epithelial-to-mesenchymal transition that leads to cancer metastasis or regulating tumor immune responses. Thank you for your contribution to the community.


Leena Hilakivi-Clarke, Anni Wärri, Kerrie B. Bouker, Xiyuan Zhang, Katherine L. Cook, Lu Jin, Alan Zwart, Nguyen Nguyen, Rong Hu, M. Idalia Cruz, Sonia de Assis, Xiao Wang, Jason Xuan, Yue Wang, Bryan Wehrenberg, Robert Clarke.Effects of In Utero Exposure to Ethinyl Estradiol on Tamoxifen Resistance and Breast Cancer Recurrence in a Preclinical Model. Journal of the National Cancer Institute, 2016; 109 (1): djw188 DOI: 10.1093/jnci/djw188

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Last Updated on September 13, 2016 by Marie Benz MD FAAD