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Cyclin D1 Regulation of Nuclear Receptor Function
Patients receiving adjuvant tamoxifen whose tumors express high levels of both HER2/neu (HER2) and the estrogen receptor (ER) often develop tamoxifen resistance. We used a mouse breast cancer model system with high ErbB2 expression to investigate the possible mechanisms underlying this resistance. The ErbB2 transmembrane receptor is overexpressed in -30% of human tumors. Approximately 15% of ERa+ human tumors express ErbB2 and ErbB2 activates ERa. Mammary gland targeted ErbB2 overexpression is sufficient for mammary tumorigenesis in vivo. Cyclin D1 anti-sense blocks ErbB2 tumor growth and ablation of the cyclin D1 gene in mice abrogates terminal alveolar breast bud development, in addition to ErbB2-induced tumor growth. We show cyclin D1-/- mice have substantial genetic and phenotypic changes reflecting altered activity of the ERa, implicating this ERa signaling in the tumor resistant phenotype. The cyclin D1 gene product is overexpressed in 30-50% of human breast cancers. Cyclin D1 physically interacts with nuclear hormone receptors (NHR), the estrogen receptora (ERa), androgen receptor (AR), and peroxisome proliferator-activated receptor gamma (PPARg) to regulate their activity. The holoenzyme-independent functions of cyclin D1 have been proposed to contribute to mammary tumor growth. Cyclin D1 activates ERa activity and coexpression of cyclin D1 with ERa correlates with poor prognosis. Aim 1. Determine the mechanisms by which cyclin D1 regulates ERa function. Aim 2. Determine the role of ErbB2 and cyclin D1 in breast cancer resistance to tamoxifen treatment. The current studies will use inducible transgenics to identify the molecular mechanisms by which cyclin D1 regulates ERa function and development of resistance to chemotherapy. We will determine the mechanisms governing cyclin D1-ERa function in vivo. The role of ERa acetylation in ErbB2 tumorigenesis will be analyzed in cultured cells and during mammary tumor onset and progression. We will determine the functional interactions between ErbB2 and the ERa wt in cultured cells and in inducible transgenic mice.
Inhibition of ERa action by the antiestrogen drug, tamoxifen, represents a major therapeutic and preventative strategy for breast cancer. However, a frequent clinical problem is antiestrogen treatment failure, which is associated with breast carcinomas that exhibit a positive hormonal receptor status yet are not responsive to treatment or more commonly that develop resistance. An important first step is to identify whether the ERa gene itself and its signaling partners become misregulated in human breast cancer and how locally acting genes can impinge on ERa activity. Specifically, the study will focus on two locally acting cellular genes thought to be intimately involved in breast neoplasia, the cyclin D1 and ErbB2 genes. The unifying theme of the current study is that underlying the ability of cyclin D1 and ErbB2 to control breast cancer cell proliferation may be the regulation of ERa function, a poorly understood area. The properties of the cyclin D1 and ErbB2 genes that make them interesting candidates, is accumulating evidence that both genes can modulate nuclear receptor function and the realization that for the ERa these interactions may be clinically important in determining overall hormonal responsiveness. Firstly, defined properties of ERa function and their regulation by cyclin D1 and ErbB2 will be examined using well-established assays for analyzing specific protein functions and interactions. This basic foundation will be extrapolated by the exploratory power of gene microarray analysis applied to mammary gland targeted mouse models, in which the activation or inactivation of the specific genes in question (normal/mutant ERa, cyclin D1 and ErbB2) can be experimentally controlled alone and in conjunction. Thus, allowing for the consequences of such protein interactions to be corroborated in mammary gland development and the cancer process in vivo. By linking the gene expression profiles generated from these mouse models with a detailed molecular pathological characterization, novel aspects of the interaction between the endocrine and locally acting factors under study will be highlighted. It is hoped that the molecular dissection of the interactions between the cyclin D1 and ErbB2 genes with ERa may ultimately illuminate concepts of neoplastic breast disease or antiestrogen treatment failure, thus facilitating the development of novel therapeutic and diagnostic targets and/or the refinement of existing hormonal interventions.