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    Research Grants Awarded

    Recruitment and Activation of the SWI/SNF Chromatin Remodeling Complex at Estrogen Receptor-regulated Promoters in Breast Cancer Cells

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    Abnormal transcriptional regulation of estrogen target genes is an important etiology in breast cancer, the most frequently diagnosed cancer in women. For example, transcriptional coregulatory proteins (e.g., SRC proteins such as AIB1) play an important role in both the estrogen-dependent onset of the disease and in the response to estrogen receptor (ER)-targeted drugs (e.g., selective estrogen receptor modulators, SERMs). SWI/SNF, a chromatin remodeling complex, is a transcriptional coregulator important for ER-dependent transcription. Although components of SWI/SNF can affect SERM-dependent responses by ER, the mechanisms underlying these effects and their importance in breast cancer have not been well defined. In particular, the mechanisms by which SWI/SNF is recruited to estrogen-regulated genes and is activated by ER are not understood. SWI/SNF contains multiple protein subunits, including a well-studied ATPase (i.e., Brg1 or Brm) that drives chromatin remodeling and gene regulation. The functions of most of the other subunits, however, have not been elucidated. I propose to study the role of BAF60a, a SWI/SNF subunit that has recently been shown to bind directly to ER. I hypothesize that: (1) both BAF60a and ER are important for ligand-dependent recruitment and activation of SWI/SNF at ER-regulated promoters and (2) the estrogen target promoters themselves will differentially effect the recruitment and/or activity of the SWI/SNF complex. These two hypotheses will be tested in corresponding specific aims using a complementary set of biochemical and cell-based assays. The biochemical assays will include in vitro chromatin assembly, remodeling, and transcription assays to assess ER- and BAF60a-dependent recruitment of SWI/SNF and chromatin remodeling at estrogen-regulated promoters. The cell-based assays will include a global approach (i.e., chromatin immunoprecipitation coupled with promoter microarrays; "ChIP-chip") to assess ER- and BAF60a-dependent recruitment of SWI/SNF to estrogen-regulated promoters in breast cancer cells. In both approaches, I will examine the effects of multiple ligands, including SERMs, since different ligands are likely to differentially affect the recruitment or activity of SWI/SNF in a cell type-specific manner. Results from these studies will provide new information on the role of SWI/SNF in the ligand-dependent regulation of gene expression by ER and have implications for the use of SERMs in the treatment of breast cancers.

    Lay Abstract:
    Breast cancer is the most common form of cancer diagnosed in women, and an increased lifetime exposure to estrogens is a risk factor for the development of the disease. To improve the treatments and clinical outcomes of this disease, we need a better understanding of the mechanisms by which estrogens promote the growth and proliferation of breast cancer cells. Estrogens are hormones (small molecules) that transmit physiological signals in the body. Within cells, estrogens bind to estrogen receptor ("ER") proteins, which then interact with accessory proteins (“coactivators”) critical for estrogen-dependent gene expression. Abnormal regulation of estrogen target genes is a common etiology in breast cancer. Thus, numerous studies have assessed the role of estrogen-dependent gene regulation in breast cancer, leading to valuable findings with important clinical applications. For example, coactivators (e.g., "Aimplified in Breast Cancer-1", AIB1) have been shown to play an important role in both the estrogen-dependent onset of the disease and the response to estrogen receptor (ER)-targeted drugs (e.g., selective estrogen receptor modulators, SERMs). However, the molecular mechanisms underlying ligand-dependent gene regulation in breast cancer cells, including the roles of specific coactivators, remain poorly understood. The SWI/SNF complex, a coactivator for ER, functions to increase the accessibility of genomic DNA to gene regulatory proteins including the ER. Without this complex, estrogen-dependent gene regulation is very inefficient. Although the SWI/SNF complex has been shown to play an important role in the expression of estrogen-regulated genes, the mechanisms by which it is recruited to these genes and is activated by ER are not fully understood. Therefore, the main objective of my proposal is to study the recruitment and activation of the SWI/SNF complex by the ER during ligand-dependent gene expression. In my experiments, I will use multiple ER-targeted drugs, including the SERMs tamoxifen and raloxifene, which are used as therapeutics for breast cancer. Estrogens and SERMs should have different affects on SWI/SNF complex recruitment and/or activation, which may underlie the different physiological effects of these ligands in breast tissues. Results from these studies will provide new information on the role of SWI/SNF in the ligand-dependent regulation of gene expression by ER and have implications for the use of SERMs in the treatment of breast cancers.