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Novel genomic approaches to understanding and preventing resistance to selective estrogen receptor modulators (SERMs) in breast cancer
To understand and to prevent tamoxifen resistance in breast cancer, it is important to understand the mechanisms that cause reoccurrence of breast cancer after hormone therapy. The response to inflammatory stimulation of prostate cancer proves to provide a mechanism for prostate cancer resistance. In this current application, using similar strategy, I propose a series of experiments to determine whether the interactions with macrophages provide inflammatory signals in breast cancer cells and to define molecular strategies that may link breast cancer resistance and inflammatory signals in breast cancer. It has been demonstrated that upon the binding of tamoxifen, ER binds to N-CoR effectively and blocks transcription. However, in the absence of N-CoR, it has been reported that tamoxifen is converted from an antagonist to an agonist, causing gene activation mediated by ERalpha. The ability of N-CoR to enforce repressor on ERalpha mediated function suggests that N-CoR may play a critical role in acquired resistance to tamoxifen treatment. I hypothesize that the regulation of N-CoR function is centrally involved in such events and that molecules present in the N-CoR complex play a critical role in the control of N-CoR function upon inflammatory stimuli. Understanding the roles of the proteins found to complexes with N-CoR and determining if they exert universal or selective effects on a suggested component of ERalpha, is required to decipher their potential roles in integrating signal response. Our recent observations showed that inflammatory signal cause dismissal of N-CoR, which is mediated by MEKK1 and TAB2 phosphorylation; however, TAB2 is also involved in ubiquitination of TRAF6, which results in derepression of NF-kB-mediated transcription. Thus, I will explore whether ubiquitination TRAF6 by TAB2 and its following pathway provide another mechanism of conversion of antagonists function to agonists, since the identification of the potential strategies of ERalpha corepressors dismissal and methods to maintain their association with ERalpha is important therapeutic effectiveness of SERMs. In addition, I will examine the role of GPS2, a component of the N-CoR/SMRT complex, in regulation of ERalpha target genes. I will determine a cohort of GPS2 target genes using a novel genome-wide promoter location assay recently developed in our laboratory collaboration with the Fu laboratory (UCSD). Chromatin architectural changes of MCF7 cells treated with E2 or tamoxifen will also be examined after GPS2 siRNA treatment. These will provide new insights to transcriptional regulation in breast cancer and in therapeutic approaches for tamoxifen resistances.
Breast cancer is the most common cancer among women in western countries. Estrogens are steroid hormones that influence growth, development, and function of the normal mammary gland, and are also involved in breast cancer initiation and progression. Estrogen receptor (ER) is a member of the steroid receptor family of transcription factors that mediates the response to estrogens. Thus, inhibition of ER action has become one of the major strategies for the treatment of breast cancer. However, most patients, after long treatment of anti-estrogen drugs such as tamoxifen, often develop drug resistance. As a consequence, understanding the precise mechanisms of that mediate tamoxifen resistance in breast cancer has become a central issue in breast cancer biology. Our laboratory recently showed that inflammatory stimuli provided by macrophages to cancer cells are involved in mediating resistance in prostate cancer. In this proposal, I will apply similar strategies to establish how contact with macrophage can provide inflammatory stimuli in breast cancer cells, identifying molecular mechanisms that may link inflammatory signals to switch of estrogen antagonist function to agonist. In addition, introducing a novel genome-wide promoter localizing technique, a sensitive method even usable on biopsy samples derived from breast cancer patients that developed in our laboratory in collaboration with the Fu laboratory (UCSD), I will explore target genes of GPS2 that is found to be associated with N-CoR which is proved to be required for the inhibitory function of estrogen receptor antagonists such as tamoxifen. I will also examine the chromatin structure in response to estrogen or tamoxifen. Subsequently, the changes of chromatin structure by knockdown of GPS2 will also be examined using a novel technology referred as multicolor fluorescence in situ hybridization employing a principal quantum dot detection method. These will provide new insights into breast cancer resistance and introduce a powerful technology that can be applied to detect new diagnostic markers.