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Cross-Talk Between ER Coregulators and Growth Factor Pathways in Breast Cancer Endocrine Resistance
Background: Endocrine therapy is the most effective treatment for estrogen receptor positive breast cancer. A major clinical problem, however, is intrinsic or acquired resistance to these therapies. Recent discoveries emphasize that levels of both ER coregulatory proteins and its multiple regulatory interactions with growth factor signaling pathways may be important in breast cancer endocrine resistance but the molecular mechanisms are still poorly comprehended. Objective: The objective of this project is to elucidate the key components of growth factor signaling and estrogen receptor coregulators involved in endocrine response and resistance in breast cancer. Specific Aims: (1) To decipher the expression patterns of various coactivators and corepressors, their activity and to determine their differential recruitment to the ER-ERE on key estrogen responsive genes, (2) to examine the relationship between ER coregulators and various growth factors and kinase networks, (3) to test the contribution of various key proteins and molecular profiling of breast cancer cells using nanodevices during endocrine response and resistance. Study design: The expression patterns and differential recruitment of various coregulators in tamoxifen sensitive and resistant breast cancer cells and tumors will be analyzed using immunoblotting and ChIP assay. The relationship between ER coregulatory proteins and signal transduction pathways will be examined by selectively inhibiting various pathways using specific inhibitors. Once the potential participating proteins (corepressors, coactivators, kinases) are deciphered using ChIP assay and various activity assays, their contribution to the development of endocrine resistance will be determined using small interference RNA. For cancer biomarker applications, molecular beacon probes and quantum dots will be conjugated with biomolecules such as oligonucleotides, peptides and antibodies targeted against the key proteins identified in this study. Potential Outcomes and Benefits of the Research: The studies proposed here are designed to elucidate the factors determining the intricate regulation of mixed agonist/antagonist activity of SERMs in resistant breast tumors. Our studies will also systematically examine the key proteins using two types of nanoparticle probes, molecular beacons and quantum dots. These new tools could be an important supplement to the currently available predictive markers in breast cancer. Also, therapies including specific inhibitors or down-regulators targeting coregulatory proteins are potential new treatment avenues.
Breast cancer is the most prevalent cancer in American women. Mounting evidence from various studies has underlined the importance of estrogen receptor in mammary development as well as initiation and progression of breast cancer. Only 50% of all estrogen receptor positive tumors are responsive to antiestrogens such as tamoxifen; furthermore, initially responsive tumors eventually become resistant to endocrine treatment, leading to tumor progression and death. Thus, it is imperative to understand the mechanisms responsible for resistance and to explore new therapeutic strategies for the welfare of breast cancer patients. Recent studies have shown that ligand- bound ER depending upon the nature of the ligand, recruits and interacts with specific subset of coregulatory proteins. Cross-talk between ER coregulators and various growth factor signaling pathways is an important feature in endocrine response and resistance in breast cancer. Thus the objective of this project is to elucidate the key proteins and pathways involved in resistance. The first aim will characterize these coregulatory proteins and their interaction with estrogen receptor using tamoxifen sensitive and resistant breast cancer cell lines and tumors. In the second aim, we will examine the relationship between the ER coregulators and various growth factor signaling pathways using specific inhibitors. The third aim is to test the contribution of various key players during endocrine resistance by silencing specific genes. Also, nanotechnology will be used to assess the function of key proteins. Novel nanodevices such as molecular beacon probes and semiconductor quantum dots bound with select biomolecules will be used to profile tamoxifen resistant and sensitive breast cancer cells and tumors. The results of these experiments will lead to better understanding of the key regulatory proteins and their relationship with various signal transduction pathways involved in the endocrine resistance thus enhancing our knowledge about hormone resistant breast cancer. Also, molecular profiling of the tumors using nanodevices could be used as new tools to profile tumors, to develop signature profile for the poor/good prognosis of breast cancer tumors from the endocrine therapy perspective.