Details

Autor(en) / Beteiligte

• Reese, Jordan M

Titel

Elucidating the Tumor Suppressive Effects of Estrogen Receptor Beta in Breast Cancer

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2017

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Despite over 40 years of clinical research and advances, breast cancer remains the leading cause of cancer-related deaths in women worldwide. This year alone, more than 250,000 women will be diagnosed with invasive breast cancer and approximately 40,000 women will succumb to the disease in the United States. Therefore, it is important to further our understanding of the molecular mechanisms driving the development and progression of this disease and to identify novel therapeutic targets based on these findings. The central focus of this dissertation is to elucidate the biological functions of estrogen receptor beta (ERβ) in breast cancer. ERβ is found in all subtypes of breast cancer and acts of as a tumor suppressor; however, its molecular mechanisms of action have yet to be fully understood. In Chapters 2 and 3 of this dissertation, I present data relating to the expression of ERβ in both estrogen receptor alpha (ERα)-positive breast cancer and triple negative breast cancer (TNBC). The biological effects of therapeutically targeting ERβ appear to be critically correlated with the presence of ERα. Clinically, patients with expression of both ERα and ERβ exhibited lower rates of disease recurrence when treated with 5 years of tamoxifen. These data are supported by preclinical observations demonstrating that MCF7 cells expressing both receptors showed enhanced response to classic anti-estrogenic therapies such as endoxifen, 4-hydroxytamoxifen (4HT) and Fulvestrant (ICI). However, in TNBC where ERα is absent, ERβ functions differently. Activation of ERβ with estrogen or an ERβ selective agonist decreases proliferation, invasion and migration in ERβ-positive TNBC model systems. Furthermore, in an in vivo TNBC mouse model of metastasis, estrogen treatment prevented lung colonization following tail vein injection of ERβ+ TNBC. Chapter 3 delves into a possible mechanism by which ERβ elicits these tumor suppressive effects in TNBC. Decreased proliferation, invasion and migration are shown to be mediated in part by the induction of a family of cysteine proteases known as cystatins. ChIP-sequencing revealed ERβ-binding sites within the promoter and intronic regions of each of these genes, indicating that they are direct ERβ targets. Cystatins are small secreted molecules that can elicit autocrine and paracrine effects on the tumor microenvironment. Specifically, my data reveal that cystatins interact with transforming growth factor beta receptor 2 (TGFβR2) and alter downstream canonical TGFβ signaling. Cystatins are also shown to block TGFβ-induced cell invasion, effects that were even more pronounced than those of a TGFβ inhibitor. Finally, in Chapter 4, I demonstrate that ERβ also suppresses cyclin-dependent kinases (CDK) 1 and 7. CDKs are important factors that regulate cell cycle progression. Specifically, CDK1 permits cells to enter mitosis and is the only CDK that is required for cell cycle progression while CDK7 primarily plays a role in modulating gene transcription. My studies reveal that ligand-mediated activation of ERβ with estrogen or an ERβ selective agonist decreases CDK1 and 7 expression and induces cell cycle arrest. Therefore, I explored the effect of inhibiting both CDK1 and CDK7 in TNBC. siRNA or drug-mediated inhibition of CDK1 and CDK7 resulted in decreased proliferation, however inhibition of CDK7 had no effect on cell cycle arrest. These effects were independent of ER? expression and lend support to the notion that CDK1 and/or CDK7 are relevant therapeutic targets for TNBC. Overall this body of work increases our understanding of the role of ERβ in breast cancer, specifically in TNBC. Since TNBC is highly aggressive and therapeutic options are limited, targeting ERβ or CDKs offer new strategies for the treatment of patients with this form of the disease.