Role of AIB3 in Mammary Gland and Breast Cancer

描述（由申请人提供）：乳腺癌中的转录因子-3（AIB 3）是一种乳腺癌扩增和过表达的核受体（包括雌激素（E）和孕酮（P）受体（ER α和PR））的强转录共激活因子。我们的数据表明，ER α和PR的转录能力在AIB 3缺陷细胞中显著受损; AIB 3在乳腺上皮细胞中高度表达，并在癌基因诱导的乳腺肿瘤细胞中进一步增加。因此，我们推测AIB 3通过其LXXLL基序与ER α和PR的相互作用，在E和P调节的乳腺发育和乳腺癌的激素促进中起重要作用。为了验证我们的假设，我们计划进行三个具体的目标：（1）表征AIB 3在ER α和PR介导的乳腺发育和基因表达中的作用;（2）评估AIB 3的LXXLL基序在乳腺中ER α和PR介导的生物学功能中的作用;和（3）确定AIB 3在乳腺癌发生的激素促进中的作用。在追求目标1中，我们计划通过在PR启动子的控制下表达Cre重组酶，在小鼠ER α/PR阳性乳腺上皮细胞中特异性地删除floxed AIB 3基因。通过比较条件性AIB 3突变乳腺与正常乳腺的表型，将确定AIB 3在E/P调节的乳腺发育、激素敏感性以及ER α和PR靶基因表达中的生理功能。在追求目标2时，将在小鼠中分别突变AIB 3中的第一和第二LXXLL基序，并且将通过分析这些突变对乳腺发育、E刺激的乳腺导管生长、P刺激的肺泡发育和激素应答基因的表达的影响来表征它们在乳腺中ER α和PR功能中的作用。在追求目标3时，将通过在乳腺上皮细胞中表达致癌转基因和通过使用化学致癌物在条件AIB 3突变小鼠和对照小鼠中诱导乳腺癌。如果AIB 3在乳腺癌的激素促进中起作用，PR/ER α阳性乳腺上皮细胞中AIB 3的失活应该抑制由升高的E & P促进的乳腺肿瘤发生。我们还将在乳腺肿瘤细胞中检测AIB 3，并测试使用AIB 3作为乳腺癌治疗靶点的可能性。通过这些研究，我们将深入了解AIB 3在ER α和PR介导的乳腺发育、基因表达和激素促进乳腺癌中的体内作用和分子机制。AIB 3作为乳腺癌的癌基因和乳腺癌治疗的分子靶点是非常有希望的。

DESCRIPTION (provided by applicant): 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.