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    Research Grants Awarded

    Distinct function and role of androgen receptor cofactor ARA70alpha and ARA70beta isoforms in breast cancer growth and metastasis

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    Background: Our goal is to elucidate the molecular mechanism and function of the androgen receptor (AR) coactivator ARA70 in breast cancer growth, metastasis and Herceptin respon-siveness. Decreased expression of a ndrogen receptor coactivator ARA70 a was shown to be associated with a subset of Her2/neu positive breast cancer and tendency of breast cancer metastasis. ARA70 b is increased in breast cancer, suggesting that two isforms of ARA70, full-length ARA70 a and internally spliced form ARA70 b , have distinct, even contrasting, effects in the regulation of breast cancer growth and metastasis. Objective/Hypothesis: We hypothesize that that two isforms of ARA70, full-length ARA70 a and internally spliced form ARA70 b , may have distinct, even contrasting, effects in the regulation of breast cancer growth, metastasis and Herceptin responsiveness. Specific Aims: To elucidate the functional relevance of ARA70 a and ARA70 b in growth, metastatic and Herceptin resistant breast cancer, we will 1 ) test if ARA70 a induces growth arrest and ARA70 b promotes cell growth in the breast cell lines and nude mice xenografts. 2) test if decreased ARA70 a and/or increased ARA70 b is associated with breast cancer invasion/metastasis. 3) determine the association between human breast cancer metastasis, and Trastuzumab resistance and altered expression of ARA70 a and ARA70 b . Study Design: We will establish immortalized benign MCF 1 0A, a less malignant MCF7 and highly malignant MDA-MB-435 breast cell lines with increased and decreased (using RNA interference technology) expression of ARA70 a and ARA70 b using retroviral vectors, pBabe or pBabe/U6. The effects of ARA70 a and ARA70 b on cancer growth, invasion, metastasis will be determined by in vitro (cell proliferation, anchorage-independent and Matrigel invasion) and in vivo (nude mice xenograft) assays. Most importantly, we will determine the association between the clinical outcomes of breast cancer (metastasis and Herceptin-resistance) and altered levels of ARA70 a and ARA70 b expression by immunohistochemistry using ARA70 a and ARA70 b specific antibodies. Potential outcomes and benefits of research: Our study will elucidate the mechanism of ARA70's effects in breast cancer and provide the rational basis for the use of ARA70 a and ARA70 b as prognostic markers and as a new therapeutic strategy, targeting AR cofactors such as ARA70 that act downstream of hormones and hormone receptors.

    Lay Abstract:
    Our goal is to elucidate the molecular mechanism of the AR coactivator ARA70 in breast cancer. The results of our preliminary studies suggested that the two isoforms of ARA70, the full-length (ARA70 a ) and internally spliced (ARA70 b ) forms, might have distinct, even contrasting, effects on the regulation of breast cancer growth rand metastasis. To elucidate the functional relevance of ARA70 a and ARA70 b in breast cancer, we will test our hypothesis that ARA70 a and ARA70 b differentially regulate breast cancer growth, invasion and metastasis using cell lines, and we will determine the role of altered ARA70 a and ARA70 b expression in human metastatic breast cancer and treatment outcome with trastuzumab . To accomplish the above, w e will first determine precisely what the regulatory effects of ARA70 a and ARA70 b on growth, invasion and metastasis of breast cancer are using both in vitro (cell proliferation and anchorage-independent) and in vivo (nude mice xenograft) assays. Specifically, we will generate stably transfected benign immortalized (MCF10A) and malignant (MCF7 and MDA-MB-435) breast cell lines with increased and decreased expression of ARA70 a and ARA70 b , using the mammalian expression system. Secondly, we will use ARA70 a - and ARA70 b -specific antibodies to determine ARA70 a and ARA70 b expression in breast cancer by immuno-histochemical tests. To associate altered ARA70 expression with metastatic cancer, we will compare the patterns of ARA70 a and ARA70 b expression using a case-control design with patients who have experienced metastasis after mastectomy and those with no evidence of metastasis for at least 5 years. To determine the relationship between ARA70 expression and trastuzumab treatment outcome, we will select HER2/neu-negative and HER2/neu-positive cases treated with trastuzumab and further grouped as trastuzumab responsive and trastuzumab nonresponsive. The comprehensive state-of-the-art approach of our study will elucidate the mechanism and function of AR coactivator ARA70 in relation to breast cancer growth, metastasis, and treatment outcome. The proposed experiments will provide a scientific rationale for the use of ARA70 a and ARA70 b as novel markers with prognostic or predictive value in breast cancer. These experiments will also provide new approaches to the design of agents that block the growth of breast cancer cells by targeting proteins that are downstream of the hormone ligand-receptor interaction.