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    Research Grants Awarded

    The Biological Role of Transcriptional Corepressor SMRT in Breast Cancer Pathogenesis and Tamoxifen Resistance

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Breast cancer is the most commonly diagnosed non-skin cancer and the second leading cause of death in women. It is widely accepted that the estrogen receptor (ER) plays a critical role in breast cancer initiation and progression. In addition, other nuclear receptor superfamily members including ERR, PPARg, RAR, RXR and PXR have also been implicated in breast cancer pathogenesis. The transcriptional activities of nuclear receptors are regulated by their association with coactivators and corepressors in a manner that is controlled by ligands. Consistent with their roles in enhancing ER transcriptional activity, the steroid receptor coactivators such as ACTR/AIB-1 isolated in Evans and Meltzer labs are amplified in breast cancers and contribute to the progression of the disease. In contrast, the roles of the corepressors in breast cancer development remain unclear. The corepressors SMRT and its homolog N-CoR function as platform proteins to recruit histone deacetylases and chromatin remodeling factors to nuclear receptors in order to execute their repressive activities. The well-characterized role of SMRT in several types of leukemia has demonstrated its importance in regulating cell proliferation, differentiation and tumor formation. Moreover, antiestrogen treatments for breast cancer such as tamoxifen (TAM) are believed to act by promoting SMRT and ER association to block estrogen mediated gene activation. Despite the relative safety and significant antineoplastic activity of tamoxifen, most responsive breast tumors eventually acquire resistance. Thus, it is reasonable to speculate that SMRT is a critical mediator of breast cancer pathogenesis. The goal of this work is to characterize the molecular nature of SMRT action toward a better understanding of its role in breast tumor progression and treatment. Objective/hypothesis: we predict that corepressor SMRT plays an important role in breast cancer pathogenesis, progression as well as TAM resistance. The main objective of this study is to establish the role of SMRT in breast cancer development and determine the molecular mechanisms that trigger the aberrant SMRT activity in TAM resistance. Specific aims: we aim to 1) establish the role of SMRT in breast cancer tumorigenesis and development. 2) determine the downstream target genes regulated by SMRT in breast caner. 3) determine the molecular mechanisms that cause the deregulated SMRT activity in TAM resistant cells. Study design: we will first isolate mouse primary mammary epithelial cells and knockdown SMRT by siRNA. We will then transform these cells and determine the role of SMRT in breast cancer development in vitro. In addition, a nuclear receptor binding deficient mutation SMRT knockin mouse model has been created in our lab. We will cross this mouse strain with ER positive breast cancer prone mice, and the breast cancer formation and progression will be assessed in vivo to determine if SMRT plays a role during these processes. To gain insight into how SMRT functions in breast cancer, we will use a functional genomics approach that combines the CHIP-on-CHIP and gene profile microarray to search for the SMRT regulated genes important in the breast cancer development. We will further use computational analysis to determine the specific nuclear receptor regulated pathways that mediate SMRT activity. In the last aim, we will use proteomic approaches to determine the molecular events that contribute to the dysregulated SMRT activity in TAM resistant cells. Potential Outcomes and Benefits of the Research: This study will help us to establish the role of SMRT during breast cancer pathogenesis and progression, and to gain insight into how SMRT contributes to the initiation and progression of breast cancer. We anticipate that this study will lead to a better understanding of the role of corepressor in breast cancer and with the long-term goal of developing more successful treatments for the disease.

    Lay Abstract:
    Breast cancer is the most commonly diagnosed non-skin cancer in women. One out of every eight women will develop breast cancer in her lifetime, and it is the second leading cause of death in women. Estrogen and its receptor (ER) have been studied extensively for their essential roles in promoting breast cancer initiation and progression. ER is one of the nuclear hormone receptor superfamily members. These receptor proteins share common structures and functional mechanisms in that they all bind to ligands and regulate gene expression. In addition to ER, other nuclear receptors, such as RAR, RXR, PR, ERR, PPARg, also have also been implicated in breast cancer formation and development. Thus, a better understanding of the regulation of these nuclear receptor family members is critical to elucidate the molecular mechanisms that control breast cancer growth and to identify novel therapeutic targets. The activities of the nuclear receptor family members are controlled by two groups of proteins called coactivators and corepressors. Coactivator proteins, which enhance ER and other nuclear receptors mediated gene expression, have been shown to promote breast cancer. However, the roles of corepressor proteins in breast cancer remain unclear. Corepressor SMRT can interact with several nuclear receptors including ER, and inhibit their activities. Antiestrogen treatments of breast cancer such as tamoxifen (TAM) can promote the interaction between SMRT and ER. However, most breast cancer patients eventually develop resistance to tamoxifen, but the mechanism is not clear. Objective/hypothesis: we propose that SMRT plays an important role in breast cancer formation, development and tamoxifen resistance. The objective of this study is to establish the function of SMRT in breast cancer and determine the specific pathways and target genes that mediate SMRT activity in breast cancer formation and development. In addition, we will also determine the molecular mechanisms that trigger the aberrant SMRT activity in TAM resistance. At first, cells from the mouse mammary gland will be isolated. We will use a gene silencing technology to eliminate SMRT inside these cells. These cells will then be transformed into cancer cells and we will assess several parameters of breast cancer development to determine if SMRT has any role in this process. Next, we will use a mouse model in which the SMRT has a non-functional mutation to determine if SMRT plays any role in the breast cancer development in vivo. In order to find how SMRT functions in breast cancer, we will utilize a recently developed functional genomics approach called CHIP-on-CHIP to identify the target genes regulated by SMRT. Lastly, we will search for any molecular mechanisms that cause SMRT dysregulation in TAM resistant breast cancer cells, such as abnormal interactions with other proteins or aberrant modifications on SMRT that control its activity. Overall, our proposed study will lead us to a better understanding on how SMRT functions in breast cancer formation, development and TAM resistance. It will have a great impact on identification of novel therapeutic targets for the breast cancer treatment, and allow us to find novel approaches that can reverse the resistance to TAM and make it as a more effective therapeutic agent.