AROMATASE AND BREAST CANCER

描述（由申请人提供）：芳香酶将雄激素转化为雌激素。芳香酶在乳腺癌组织中的表达水平高于在良性组织中的表达水平。肿瘤组织中的原位雌激素生物合成已被证明在促进肿瘤生长中发挥自分泌和内分泌作用。抑制原位雌激素生物合成可以通过防止乳腺肿瘤中芳香酶的表达或通过抑制芳香酶活性来实现。芳香酶在肿瘤组织和良性组织中的表达调控是不同的。根据本实验室和其他实验室的结果，我们假设在正常乳腺基质细胞中，芳香化酶的表达是由糖皮质激素调节的启动子（1.4）驱动的，启动子1.3和II的作用是由一个沉默的负调控元件抑制的。然而，在癌症组织中，cAMP产生增加，芳香化酶启动子转换为cAMP依赖启动子，即1.3和II。在Aim 1中，申请人建议基于之前资助期获得的重要信息，对乳腺癌细胞启动子1.3和启动子II的调控机制进行深入研究。假设了解启动子1.3和启动子II的调控机制将通过选择性抑制乳腺癌细胞中芳香化酶/雌激素的形成，从而导致乳腺癌治疗策略的发展。在过去的五年中，芳香化酶抑制剂已被证明优于他莫昔芬治疗激素依赖性乳腺癌。此外，甾体抑制剂和非甾体抑制剂已被证明在顺序使用时保持其疗效。在Aim 2中，申请人建议进行x射线结构分析、计算机建模和位点定向诱变实验，以确定不同抑制剂如何与芳香酶相互作用。据推测，结构-功能研究的结果将帮助我们更好地了解不同抑制剂如何与酶相互作用，并为设计用于乳腺癌治疗的下一代芳香酶抑制剂提供关键的结构信息。此外，虽然这些新一代的芳香酶抑制剂被证明对激素反应性乳腺癌的治疗有用，但对这种内分泌治疗的耐药性仍然存在。在目标3中，申请人建议对从我们的微阵列分析中获得的结果进行仔细和彻底的分析，以识别和功能确认参与抗性的基因的作用。假设这些研究将提供有关芳香酶抑制剂耐药机制的有价值的分子信息，这些信息将有助于设计减少耐药和提高芳香酶抑制剂治疗乳腺癌疗效的方法。

DESCRIPTION (provided by applicant): Aromatase converts androgen to estrogen. Aromatase is expressed at a higher level in breast cancer tissue than in benign tissue. In situ estrogen biosynthesis in tumor tissue has been shown to play both an autocrine and an endocrine role in promoting tumor growth. Suppression of in situ estrogen biosynthesis can be achieved by the prevention of aromatase expression in breast tumors or by the inhibition of aromatase activity. The regulation of aromatase expression is different in tumor tissue and benign tissue. Based on results generated from this and other laboratories, it is hypothesized that in normal breast stromal cells, aromatase expression is driven by a promoter (1.4) that is regulated by glucocorticoid, and the action of promoters 1.3 and II is suppressed by a silencer negative regulatory element. However, in cancer tissue, cAMP production increases and aromatase promoters are switched to cAMP-dependent promoters, i.e., 1.3 and II. In Aim 1, the applicant proposes to perform a thorough study to determine the regulatory mechanism of promoters 1.3 and II In breast cancer cells, based on important information obtained during the previous grant period. It is hypothesized that understanding of the regulatory mechanism of promoters 1.3 and II will lead to the development of breast cancer treatment strategies by selectively suppressing aromatase/estrogen formation in breast cancer cells. During the last five years, aromatase inhibitors have been demonstrated to be superior to tamoxifen with the treatment of hormonal dependent breast cancer. Furthermore, steroidal inhibitors and nonsteroidal inhibitors have been shown to maintain their efficacy when used sequentially. In Aim 2, the applicant proposes to perform x-ray structure analysis, computer modeling and site-directed mutagenesis experiments to determine how different inhibitors interact with aromatase. It is hypothesized that results generated from structure-function studies will help us to better understand how different inhibitors interact with the enzyme and provide critical structural information for the design of the next generation of aromatase inhibitors for breast cancer treatment. In addition, while these new generations of aromatase inhibitors are shown to be useful in the treatment of hormonal responsive breast cancer, resistance to such endocrine therapy still develop. In Aim 3, the applicant proposes to perform a careful and thorough analysis of the results obtained from our microarray analysis, to identify and functionally confirm the roles of genes Involved In resistance. It is hypothesized that these studies will produce valuable molecular information regarding the mechanisms of aromatase inhibitor resistance, and the information will help design approaches to reduce resistance and improve the efficacy of aromatase inhibitor treatments of breast cancer.