AROMATASE AND BREAST CANCER

描述（由申请人提供）： 芳香化酶将雄激素转化为雌激素。芳香化酶在乳腺癌组织中的表达水平高于良性组织。 在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起自分泌和内分泌作用。原位雌激素生物合成的抑制可以通过阻止乳腺肿瘤中芳香化酶的表达或通过抑制芳香化酶活性来实现。芳香化酶在肿瘤组织和良性组织中的表达调控不同。基于从这个实验室和其他实验室产生的结果，假设在正常乳腺基质细胞中，芳香酶表达由糖皮质激素调节的启动子（1.4）驱动，启动子1.3和II的作用被沉默负调控元件抑制。然而，在癌组织中，cAMP产生增加并且芳香酶启动子转换为cAMP依赖性启动子，即，1.3和二.在目的1中，申请人提议进行彻底的研究，以确定乳腺癌细胞中启动子1.3和II的调节机制，基于在先前资助期间获得的重要信息。据推测，了解启动子1.3和II的调节机制将导致乳腺癌治疗策略的发展，选择性抑制芳香酶/雌激素在乳腺癌细胞中的形成。在过去的五年中，芳香酶抑制剂已被证明是上级他莫昔芬与激素依赖性乳腺癌的治疗。此外，甾体类抑制剂和非甾体类抑制剂已被证明在顺序使用时保持其功效。在目的2中，申请人提出进行X射线结构分析、计算机建模和定点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，从结构-功能研究产生的结果将有助于我们更好地了解不同的抑制剂如何与酶相互作用，并为设计下一代乳腺癌治疗芳香酶抑制剂提供关键的结构信息。此外，虽然这些新一代芳香酶抑制剂显示可用于治疗激素响应性乳腺癌，但对这种内分泌疗法的抗性仍在发展。在目标3中，申请人提出对从我们的微阵列分析获得的结果进行仔细和彻底的分析，以鉴定和功能性地确认参与抗性的基因的作用。据推测，这些研究将产生有价值的分子信息芳香化酶抑制剂耐药的机制，和信息将有助于设计方法，以减少阻力和改善芳香化酶抑制剂治疗乳腺癌的疗效。

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.