The acquisition of endocrine resistance is a common obstacle in endocrine therapy of patients with estrogen receptor-? (ER?)-positive breast tumors. It has been long-suspected that anti-estrogen treatments deregulate the epigenetic machinery and play an important role in the acquired ETR process. There have been several studies that suggest an indirect relationship between hormonal manipulations, epigenetic changes, and endocrine resistance. However, a big gap remains in the molecular pathways that are initiated and established by estrogen signaling and those controlling epigenetic reprogramming enabling the endocrine resistance phenotype and cancer relapse. The goal of this proposal is to identify novel epigenetic factors and molecular mechanisms of which the deregulation by anti-estrogen therapy enables ETR and cancer relapse. The recently discovered ten-eleven translocation (TET) proteins, which catalyze 5-methylcytosine (5mC) to 5- hydorxymethylcytosine (5hmC), have provided new paradigms for the dynamic regulation of DNA methylation. The studies of ours and others have shown that the loss of TET2 promotes a more aggressive phenotype in breast cancer cells. Surprisingly, while screening for pathways that may repress TET expression, we found that estrogen E2 enhances the expression of TET2 in MCF-7 breast cancer cells. In contrast, treatment with anti- estrogen drugs, such as tamoxifen and fulvestrant, reduces the expression of TET2 in the same cells. Based on these results, we hypothesize that estrogen signaling and anti-estrogen therapy have double edged sword effects on breast cancer development and ETR. In addition to its well-documented oncogenic-promoting function, estrogen signaling directly up-regulates TET2 tumor suppressor genes. We hypothesize that endocrine resistance is gained in part by inhibiting the expression of TET2 as well as by altering 5hmC levels. To test this hypothesis, we will employ and develop new molecular, cellular, genetic and epigenetic approaches to investigate the mechanism underlying estrogen-induced TET2 upregulation (Aim1) and its influence on epigenomic programing/reprogramming (Aim2). Finally, we will examine the functional importance of the estrogen/ER?/TET2 pathway in preventing endocrine resistance in vitro and in vivo (Aim3). If successful, the outcomes of the proposed study will have a huge impact on basic and translational breast cancer research and on adjuvant breast cancer therapy. The knowledge acquired from this study will provide a new understanding of the mechanisms underlying breast cancer development and anti-estrogen therapy resistance. In particular, it will also add a new view of the function estrogen signaling and its associated epigenetic mechanisms have on breast cancer development and therapy. We expect that this project will lead to new directions that identify different drug targets to revers or reduce endocrine resistance in the future.
Targeting estrogen and estrogen receptor (ER?) pathway (anti-estrogen) has been the most frequently used non-surgical clinical approach for the treatment of ER?-positive breast cancers, endocrine therapy resistance and tumor relapse occur in a large portion of these patients. This project investigates a novel epigenetic mechanism underlying endocrine resistance in response to anti-estrogen treatment. The outcomes will pave the way for the development of new treatment options to prevent or reduce endocrine resistance in breast cancer, significantly impacting on human health and disease prevention
