COX-2 and PPARgamma: Targets for BRCA Prevention

描述(申请人提供)：环氧合酶-2(COX-2)和过氧化物酶体增殖物激活受体-伽马(PPAR-γ)已成为预防乳腺癌的有希望的候选者。我们和其他人的研究表明，乳腺癌中存在COX-2的诱导和PPARGamma的失活，它们直接或通过它们对一系列与增殖和凋亡相关的基因的协同作用而参与癌症的诱导。初步研究表明，同时针对COX-2和PPAR伽马可以抑制乳腺癌的程度优于单独针对两个分子产生的抑制作用。我们推测，同时靶向COX-2和PPAR-γ可能会协同作用，抑制乳腺癌变的发展，这将比单独靶向每个分子更有效。此外，COX-2抑制剂和/或PPARγ激动剂诱导常见的促凋亡信号通路，作为介导其癌症化学预防作用的机制。为了验证我们的假设，我们将评估一种新的PPAR伽马配体N-(9-荧基-甲氧羰基)-L-亮氨酸(F-L-亮氨酸)和COX-2抑制剂塞来昔布在预防N-甲基-N-亚硝脲(MNU)诱导的雌性SD大鼠乳腺癌中的疗效。为了阐明COX-2抑制剂和PPAR-γ配体预防乳腺癌的机制，我们将研究塞来昔布和F-L-亮氨酸(在正常组织和不同癌症阶段)对在乳腺固有凋亡信号中起关键作用的基因/蛋白质的影响。我们计划完成以下具体目标：目的1：分别测定F-L亮氨酸和塞来昔布预防大鼠乳腺癌的量效关系。目的2：确定试验药物组合对大鼠乳腺癌的协同预防效果。目的：通过评价试验药物对启动乳腺细胞凋亡信号的分子通路的影响，阐明试验药物预防乳腺癌变的机制。这是第一次详细的临床前工作，评估同时以COX-2和PPAR伽马为靶点作为预防乳腺癌的新策略。这项研究的结果可以：i)深入了解COX-2抑制剂和PPAR-γ配体之间的协同作用；ii)阐明这些药物介导癌症预防的机制；iii)为它们最终在临床上用于预防人类乳腺癌奠定基础。

DESCRIPTION (provided by applicant): Cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor-gamma (PPARgamma) have emerged as promising candidates for the prevention of breast cancer. Our studies and those of others suggest that COX-2 induction and inactivation of PPARgamma occur in breast cancer and that they contribute to cancer induction either directly or via their coordinate action on an array of proliferation- and apoptosis-related genes. Preliminary studies indicate that targeting both COX-2 and PPARgamma can inhibit mammary cancer to an extent superior to that produced by targeting each molecule alone. We hypothesize that simultaneous targeting of COX-2 and PPARgamma may act synergistically to inhibit the development of mammary gland carcinogenesis, which would be more effective than targeting each molecule alone. Furthermore, COX-2 inhibitors and/or PPARgamma-agonists induce common pro-apoptotic signaling pathways as a mechanism that mediates their cancer chemopreventive action. To test our hypothesis, we will assess the efficacy of a novel combinational regimen of the PPARgamma-ligand N-(9- fluorenyl-methyloxycarbonyl)-L-Leucine (F-L-Leu) and the COX-2 inhibitor celecoxib on the prevention of N-methyI- N-nitrosourea (MNU)-induced mammary cancer in female Sprague Dawley rats, a well-established animal model of breast cancer. To elucidate the mechanisms by which COX-2 inhibitors and PPARgamma-ligands prevent mammary cancer, the effects of celecoxib and F-L-Leu (separately and in combination) will be examined (both in normal tissues and at different cancer stages) on genes/proteins that play a critical role in mediating intrinsic apoptotic signaling in the mammary gland. We plan to accomplish the following specific aims: Aim 1: determine the dose-response effects of F-L-Leu and celecoxib, separately, on the prevention of rat mammary cancer. Aim 2: determine the synergistic preventive efficacy of a combination of the test drugs on rat mammary cancer. Aim 3: elucidate the mechanisms by which the test drugs prevent mammary gland carcinogenesis by evaluating their effects on molecular pathways that initiate apoptotic signaling in the mammary gland. This is the first detailed preclinical effort to evaluate targeting COX-2 and PPARgamma simultaneously as a novel strategy for breast cancer prevention. The results of this study can: i) provide insight into the synergistic interaction between COX-2 inhibitors and PPARgamma-ligands, ii) elucidate the mechanisms by which these agents mediate cancer prevention and iii) establish the basis for their eventual clinical use in the prevention of human breast cancer.