The amplified-in-breast cancer-3 (AIB3) is a breast cancer amplified and overexpressed strong transcriptional coactivator for nuclear receptors including estrogen (E) and progesterone (P) receptors (ERalpha and PR). Our data demonstrated that transcriptional capabilities of ERa and PR are significantly impaired in AIB3 deficient cells; AIB3 is highly expressed in the mammary epithelial cells and further increased in the oncogene-induced mammary tumor cells. Therefore, we hypothesize that AIB3 plays important roles in E and P-regulated mammary gland development and hormonal promotion of breast cancer through interaction of its LXXLL motifs with ERa & PR. To test our hypothesis, we plan to pursue three specific aims: (1) characterization of the role of AIB3 in ERalpha and PR-mediated mammary gland development and gene expression; (2) assess the role of LXXLL motifs of AIB3 in ERalpha- and PR-mediated biological functions in the mammary gland; and (3) define the role of AIB3 in hormonal promotion of mammary carcinogenesis. In pursuing aim 1, we plan to delete the floxed AIB3 gene specifically in the ERalpha/PR-positive mammary epithelial cells in mice by expressing the Cre recombinase under the control of the PR promoter. The physiological function of AIB3 in E/P-regulated mammary gland development, hormonal sensitivity and the expression of ERalpha and PR target genes will be defined through comparing phenotypes of conditional AIB3 mutant mammary glands with normal mammary glands. In pursuing aim 2, the first and the second LXXLL motifs in AIB3 will be separately mutated in mice and their roles in ERalpha and PR functions in the mammary gland will be characterized by analyzing the effects of these mutations on mammary gland development, E-stimulated mammary ductal growth, P-stimulated alveolar development and the expression of hormonal responsive genes. In pursuing aim 3, breast cancers will be induced in conditional AIB3 mutant mice and control mice by expressing an oncogenic transgene in the mammary epithelial cells and by using a chemical carcinogen. If AIB3 plays a role in hormonal promotion of breast cancer, inactivation of AIB3 in PR/ERalpha positive mammary epithelial cells should suppress mammary tumorigenesis promoted by elevated E & P. We also will inactivate AIB3 in breast tumor cells and test the possibility to use AIB3 as a target for breast cancer treatment. Through these studies, we will gain great insight into understanding of the in vivo role and molecular mechanisms of AIB3 in ERalpha and PR-mediated breast development, gene expression and hormonal promotion of breast cancer. It is very hopeful to identify AIB3 as an oncogene in the breast and a molecular target for breast cancer treatment.
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