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    Research Grants Awarded

    Regulation of ER transcriptional potential by the chromatin architectural factor HMGB1

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    Disruption of estrogen receptor (ER) signaling is a widely used strategy in breast cancer therapy. However, some breast cancer cells gradually develop resistance to endocrine therapy, at least in part due to a “transcription potent” form of ER even at low levels of circulating estrogen. We reason that ER binding to its target gene response elements, a step that is stimulated by a cellular protein HMGB1, is essential in the regulation of estrogen signaling pathways. Interestingly, HMGB1 expression varies greatly among breast cancer cells and its acetylated form exists in cancer cells but not in normal cells, suggesting that HMGB1 may be responsible for sensitizing breast cancer cells to estrogen and itself may be a potential target for treatment of breast cancer. The long-term goal of this project is to develop new therapeutics for hormone therapy resistant breast cancers. We hypothesize that HMGB1 is a key regulator in ER-dependent gene expression. Not only can it stimulate the expression of ER-target genes lacking the consensus ERE but also its acetylated form in cancer cells is more potent in transactivating ER. Thus, the constitutive activation of ER-target gene expression by HMGB1 might contribute to the resistance of breast cancer cells to hormone therapy. To test this hypothesis, we will (1) Isolate HMGB1 from normal and breast cancer cells and characterize their abilities to stimulate ER-binding to ER-responsive element. (2) Examine the ability of HMGB1 and acetylated-HMGB1 to activate ER-dependent gene expression using the in vitro reconstituted chromatin templates. (3) Demonstrate the effects of HMGB1 on the expression of endogenous ER-target genes and the importance of HMGB1 acetylation in activation of ER. The recruitment of HMGB1 to ER-target gene promoters will be examined using chromatin immunoprecipitation (ChIP) assay. Our studies will provide a better understanding of the action of ER on gene expression and elucidate the transcriptional roles of HMGB1 in breast cancer. Therapies that block the HMGB1/ER/ERE interaction, the fundamental step in ER target gene activation, are potential new treatment avenues.

    Lay Abstract:
    The steroid hormone estrogen is involved in the development and growth of a large proportion of breast cancers. Estrogen regulates gene expression by binding to its cellular receptor, known as the estrogen receptor (ER). Manipulation of that signaling by hormonal therapy has proven clinical significance in the treatment of breast cancers which express ER. However, at least 40% of ER-positive breast cancers fail to respond to hormonal therapy. The exact mechanism of breast cancer cell resistance to hormone therapy is unclear. Nevertheless, nuclear ER appears to avidly bind to its response elements on target genes to activate gene expression even under treatment with tamoxifen or aromatase inhibitors. Therefore, blocking ER-binding to its target genes would be an ultimate approach in the treatment of hormone-resistant ER-regulated breast cancer. ER-binding to its target gene response elements is the key step in regulation of estrogen-signaling. One cellular protein that facilitates ER-binding to ER-response element is HMGB1. Interestingly, HMGB1 expression varies greatly among breast cancer cells and its acetylated form is found in cancer cells but not in normal cells, implying that HMGB1 may be responsible for sensitizing breast cancer cells to estrogen. In order to define the functional roles of HMGB1 in ER-positive breast cancer cells, we will: (1) isolate HMGB1 from normal and breast cancer cells and characterize its abilities to stimulate ER-binding to ER-responsive elements in some known target genes; (2) examine the ability of HMGB1 and acetylated-HMGB1 to activate ER-dependent gene expression using a reconstituted system which largely mimics the gene structure in cells and has been proven to be faithful means for studying ER action; and (3) investigate the effects of HMGB1 on the expression of endogenous ER-target genes and the importance of HMGB1-acetylation in activation of ER. Our major hypothesis is that constitutive activation of ER-target gene expression by HMGB1 contributes to the resistance of breast cancer cells to hormonal therapy. Therefore, dissecting the functional roles of HMGB1 in ER-regulated gene expression will provide a better understanding of the link between alterations in ER-ERE association and breast cancer, thus ultimately leading to the development of improved strategies for the prevention and treatment of hormone resistant ER-positive breast cancer.