The ErbB2 transmembrane receptor is overexpressed in approximately 30% of human tumors. Mammary gland targeted ErbB2 overexpression is sufficient for mammary tumorigenesis in vivo. The cyclin D1 gene product is overexpressed in 30-50% of human breast cancers. Cyclin D1 anti-sense blocks ErbB2-induced mammary tumor growth and cyclin D1 -/- mice are resistant to ErbB2-induced tumor growth. The PPARgamma nuclear hormone receptor inhibits cellular proliferation and promotes differentiation. Mutations, rearrangements and altered expression of PPARgamma have been identified in several cancers suggesting PPARgamma may function as a tumor suppressor. We have shown cyclin D1 inhibits PPARgamma differentiation function, transactivation and expression in cultured ceils. We have shown CD1 -/- mice have genetic and phenotypic changes reflecting increased PPARgamma expression and activity, implicating increased PPARgamma in the tumor-resistant phenotype. The current studies will determine the molecular mechanisms by which cyclin D1 inhibits PPARgamma signaling in vivo. We will use mammary gland-targeted inducible transgenics to identify the molecular mechanisms by which cyclin D1 regulates PPARgamma function and determine the role of PPARgamma as a mammary gland tumor suppressor in the context of ErbB2. These studies will: 1. Determine the mechanism by which cyclin D1 inhibits PPARgamma transactivation. The ability of cyclin D1 to inhibit a subset of PPARgamma coactivators will be determined. As PPARgamma is acetylated and the cyclin D1 HDAC recruitment domain governs PPARgamma repression, the role of PPARgamma acetylation in repression by cyclin D1 will be determined. 2. Determine the mechanisms by which cyclin D1 inhibits PPARgamma function and expression. Cyclin D1 blocks PPARgamma induced differentiation of fibroblasts to adipocytes. We will identify the domain of cyclin D1 regulating PPARgamma differentiation. Cyclin D1 regulation of PPARgamma will be assessed in CD-/- mice, cyclin E knockin-CD-/- mice and in ponasterone-inducible cyclin D1 anti-sense mice. Correlative expression studies of PPARgamma and cyclin D1 will be conducted in 'benign' breast disease and breast cancers. 3. Determine the role of PPARgamma as a tumor suppressor of ErbB2-induced mammary tumorigenesis. We will determine the functional interactions between ErbB2 and PPARgamma in cultured cells and in ponasterone-inducible mammary gland-targeted PPARgamma transgenic mice. The use of inducible transgenics will allow the determination of PPARgamma function during mammary tumor onset and progression. If PPARgamma is an inhibitor of ErbB2-induced tumorigenesis and PPARgamma tumor suppressor function involves cyclin D1 repression, these studies provide a rational basis for identifying agonists of this interaction for potential therapeutic applications. Moreover, if PPARgamma levels are decreased in precursor lesions of breast cancer, the studies of PPARgamma in benign breast disease may provide a predictor of breast cancer progression. The proposed studies therefore may have important translational implications.
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