In Utero Estrogen Exposure Increases Antiestrogen Resistance by Inducing EMT
Annual rept. 15 Jan 2014-14 Jan 2015
GEORGETOWN UNIV WASHINGTON DC
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Endocrine therapies such as antiestrogens AE are widely used in estrogen receptor positive ER breast cancer, due to their efficacy and limited toxicity. However, the clinical reality is that of the 50 of ER patients that initially respond to these therapies, many will acquire resistance and recur. The causes of antiestrogen resistance are currently unclear. Our recent preclinical study found that maternal exposure to excess estrogens during pregnancy increases the risk that AE resistance in ER mammary tumors in the offspring. This increase may be caused by epigenetic mechanisms, such as an increase in DNA methyltransferases DNMT and methylation, and histone deacetylases HDAC and histone modifications. In this study, our preliminary data show not only an increase in TAM resistance in rats exposed to in utero estrogen, but concurrent treatment with DNMT and HDAC inhibitors inhibited this resistance, suggesting that epigenetic changes driven by estrogenic exposures early in life may preprogram the breast to develop tumors with a higher propensity to develop antiestrogen resistance.
- Medicine and Medical Research