Modulation of aromatase: implications for breast cancer

项目概述：乳腺癌抗雌激素耐药可能是由生长因子受体信号通路与雌激素通路的串扰引起的。我们最近的数据表明，芳香化酶的酶活性可以通过AKT增加，AKT是一种由几种生长因子受体酪氨酸激酶信号级联反应激活的激酶（例如HER2/Neu）。芳香酶是一种限速酶复合物，参与雌激素的生物合成，在乳腺组织中发挥有丝分裂、抗凋亡和刺激生长的作用。因此，生长因子受体信号可能调节芳香化酶活性、雌激素产生以及随后的雌激素反应通路的激活。目的1-确定AKT是否磷酸化芳香酶以增加其体外酶活性。目的2-确定活性AKT是否调节体内芳香化酶活性和芳香化酶诱导的转基因小鼠乳腺形态学改变。目的3-确定转基因小鼠乳腺上皮中活性AKT或HER2/Neu的过度表达是否赋予了对芳香酶抑制剂的抗性。目的1将利用分子技术和细胞系来确定AKT在体外磷酸化调节芳香酶的能力。目的2和3将使用转基因小鼠模型的组织形态学、免疫组织化学和分子分析来确定活性AKT和HER2/Neu是否可以调节体内芳香酶活性，以及这些癌基因是否赋予对芳香酶抑制剂的抗性。这些研究结果可能为激素依赖性癌症提供新的药物靶点，同时进一步加深我们对生长因子受体信号传导和雌激素途径之间的交流的理解。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，以治疗雌激素依赖性乳腺癌。虽然芳香酶抑制剂最初非常有效，但肿瘤通常表现出初始或获得性耐药，需要进一步开发治疗方法。我们的工作将探讨癌细胞介导芳香化酶抑制剂治疗逃逸的潜在机制，为乳腺癌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.