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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119689-02
Application #
7092206
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2005-07-08
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$289,288
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Kawagoe, Jun; Li, Qingtian; Mussi, Paola et al. (2012) Nuclear receptor coactivator-6 attenuates uterine estrogen sensitivity to permit embryo implantation. Dev Cell 23:858-65
Wu, Mei-Yi; Fu, Junjiang; Xu, Jianming et al. (2012) Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor. Cell Res 22:1003-21
Qin, Qian; Xu, Young; He, Tao et al. (2012) Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res 22:90-106
Hong, Jun; Zhou, Jian; Fu, Junjiang et al. (2011) Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res 71:3980-90
Qin, Li; Chen, Xian; Wu, Yelin et al. (2011) Steroid receptor coactivator-1 upregulates integrin ?? expression to promote breast cancer cell adhesion and migration. Cancer Res 71:1742-51
Fu, Junjiang; Qin, Li; He, Tao et al. (2011) The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res 21:275-89
Li, Qingtian; Xu, Jianming (2011) Identification and characterization of the alternatively spliced nuclear receptor coactivator-6 isoforms. Int J Biol Sci 7:505-16
Liu, Zhaoliang; Zhou, Suoling; Liao, Lan et al. (2010) Jmjd1a demethylase-regulated histone modification is essential for cAMP-response element modulator-regulated gene expression and spermatogenesis. J Biol Chem 285:2758-70
Wang, Wei-Lin; Li, Qingtian; Xu, Jianming et al. (2010) Lens fiber cell differentiation and denucleation are disrupted through expression of the N-terminal nuclear receptor box of NCOA6 and result in p53-dependent and p53-independent apoptosis. Mol Biol Cell 21:2453-68
Xiao, Yichuan; Xu, Jingwei; Wang, Shu et al. (2010) Genetic ablation of steroid receptor coactivator-3 promotes PPAR-beta-mediated alternative activation of microglia in experimental autoimmune encephalomyelitis. Glia 58:932-42

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