Modulation of aromatase: implications for breast cancer

描述(申请人提供)：项目摘要：乳腺癌对抗雌激素的耐药性可能是由生长因子受体信号和雌激素通路之间的串扰引起的。我们最近的数据表明，AKT可以提高芳香酶的活性，AKT是一种由几个生长因子受体酪氨酸激酶信号转导通路(如HER2/Neu)激活的激酶。芳香酶是一种参与雌激素生物合成的限速酶复合体，在乳腺组织中发挥促有丝分裂、抗凋亡和促进生长的作用。因此，生长因子受体信号可能会调节芳香酶活性、雌激素的产生，以及随后雌激素反应通路的激活。目的1-确定AKT是否在体外磷酸化芳香酶以提高其酶活性。目的2-确定活性AKT是否在体内调节芳香酶活性以及芳香酶诱导转基因小鼠乳腺的形态改变。目的3-确定转基因小鼠乳腺上皮细胞中活性AKT或HER2/Neu的过度表达是否会导致对芳香酶抑制剂的抵抗。目的1将利用分子技术和细胞系在体外测定AKT对芳香酶的磷酸化调节能力。AIMS 2和3将使用转基因小鼠模型的组织形态、免疫组织化学和分子分析来确定活性AKT和HER2/Neu是否可以调节体内的芳香酶活性，以及这些癌基因是否对芳香酶抑制剂产生耐药性。这些研究的结果可能为激素依赖型癌症提供新的药物靶点，同时加深我们对生长因子受体信号和雌激素通路之间的联系的理解。相关性：芳香酶抑制剂在临床上用于减少芳香酶介导的雌激素的产生，用于治疗雌激素依赖型乳腺癌。虽然芳香酶抑制剂最初是非常有效的，但肿瘤通常表现出初始或获得性耐药，这需要进一步的治疗方法的开发。我们的工作将研究癌细胞介导逃避芳香酶抑制剂治疗的潜在机制，为乳腺癌的治疗提供新的药物靶点。

DESCRIPTION (provided by applicant): Project Summary: Breast cancer resistance to anti-estrogens may be caused by cross-talk between growth factor receptor signaling and estrogenic pathways. Our recent data suggest that the enzymatic activity of aromatase can be increased by AKT, a kinase activated by several growth factor receptor tyrosine kinase signaling cascades (e.g., HER2/Neu). Aromatase is the rate-limiting enzyme complex involved in the biosynthesis of estrogens, which exert mitogenic, anti-apoptotic, and growth-stimulatory effects in mammary tissues. Therefore, growth factor receptor signaling may moderate aromatase activity, estrogen production, and the consequent activation of estrogen-responsive pathways. Aim 1- To determine if AKT phosphorylates aromatase to increase its enzymatic activity in vitro. Aim 2- To determine whether active AKT modulates aromatase activity in vivo and aromatase-induced morphological alterations in the mammary gland of transgenic mice. Aim 3- To determine whether over-expression of active AKT or HER2/Neu in the mammary epithelium of transgenic mice confers resistance to aromatase inhibitors. Aim 1 will utilize molecular techniques and cell lines to determine the ability of AKT to phosphoregulate aromatase in vitro. Aims 2 and 3 will use histomorphological, immunohistochemical, and molecular analyses of transgenic mouse models to determine whether active AKT and HER2/Neu can modulate aromatase activity in vivo, and whether these oncogenes confer resistance to aromatase inhibitors. Results from these studies may provide novel drug targets for hormone-dependent cancers while furthering our understanding of the communication between growth factor receptor signaling and estrogenic pathways. Relevance: Aromatase inhibitors are used clinically to decrease the aromatase-mediated production of estrogens for the treatment of estrogen-dependent breast cancers. While aromatase inhibitors are initially very effective, tumors typically exhibit initial or acquired drug resistance, necessitating the development of further therapeutics. Our work will investigate potential mechanisms by which cancer cells mediate escape from aromatase inhibitor therapy to provide new drug targets for the treatment of breast cancer.