(PQA5) 'Dose and Mechanisms of Exercise in Breast Cancer Prevention'

描述(申请人提供)：乳腺癌是美国女性最常见的恶性肿瘤，2012年新增诊断约22.9万例，死亡约3.9万例。此外，乳腺癌发病率预计将在未来20年内增加约45%。尽管他莫昔芬被认为是乳腺癌高危女性的标准化学预防策略，但在高达30%的高危女性中，它与医学上的矛盾，与几种不良反应有关，并且仅对预防雌激素受体阳性(ER+)乳腺癌有效。因此，迫切需要新的、无毒的策略来预防ER+和ER阴性(ER-)乳腺癌。观察性研究表明，在绝经前和绝经后的女性中，定期锻炼始终与ER+和ER-乳腺癌发病率降低20%-30%相关。然而，强调这种联系的宿主和/或肿瘤相关机制以及调节这些效应的最佳“剂量”尚未阐明。在此背景下，这项资助的目的是阐明运动对乳腺癌启动的抑制作用的“剂量-反应”效应，以及生长因子停用在临床前和临床研究中调节这一效应的作用。我们的中心假设是，运动以一种剂量依赖的方式，将减少宿主(外周循环)和乳腺组织中促炎症生长因子的可获得性，而这反过来将有效地抑制诱导向恶性表型转化的核心细胞信号通路。这一中心假设将通过三个翻译目标来解决，这些目标跨越了实验室和临床研究。目标1(临床前)：在基因不同的乳腺癌转基因模型中确定运动对肿瘤抑制的‘剂量-反应’；目标2(临床)：在乳腺癌高危女性(即细胞学确认的非典型性)的随机试验中确定运动训练对乳腺组织生长因子谱的‘剂量-反应’；以及目标3(机制)：使用靶向分子分析(IHC，RT-PCR)结合无偏见的方法[即，反向蛋白微阵列]来识别和验证生长因子和信号通路调节。为了测试运动诱导的生长因子停用的机制作用，我们将使用遗传(敲入模型)或药物(特异性激动型抗体)策略过度表达生长因子的可用性或生长因子受体的活性。这个子目标将通过使用暴露于AIM 2中获得的患者样本的血清的人类癌前细胞系的体外实验以及使用‘添加回来’实验的重组生长因子来解决。

DESCRIPTION (provided by applicant): Breast cancer is the most commonly diagnosed malignancy in American women with ~229,000 new diagnoses and ~39,000 deaths expected in 2012. Further, breast cancer incidence is projected to increase by ~45% over the next two decades. Although tamoxifen is considered the standard chemopreventive strategy for women at high-risk of breast cancer, it is medically contradicted in up to ~30% of high-risk women, associated with several adverse toxicities, and only effective for prevention of estrogen receptor positive (ER+) breast cancer. Thus, there is an urgent need for new, non-toxic strategies to prevent both ER+ and ER negative (ER-) breast cancer. Observational studies indicate that regular exercise is consistently associated with a 20%-30% reduction in both ER+ and ER- breast cancer incidence in both pre-and postmenopausal women. However, the host and/or tumor-related mechanisms that underline this association as well as the optimal 'dose' to modulate these effects have not been elucidated. Against this background, the objective of this grant is to elucidate the 'dose-response' effect of exercise on inhibition of breast cancer initiaton and the role of growth factor withdrawal to regulate this effect in preclinical and clinical studie. Our central hypothesis is that exercise, in a dose-dependent manner, will reduce proinflammatory growth factor availability in the host (peripheral circulation) and mammary tissue that, in turn, will effectively inhibit 'core' cell signaling pathways that induce the transtion to the malignant phenotype. This central hypothesis will be addressed by three translational aims that span laboratory to clinical studies. Aim 1 (preclinical): Determine the 'dose-response' of exercise on tumor inhibition in genetically-distinct transgenic models of breast cancer; Aim 2 (clinical): Determine the 'dose-response' of exercise training on mammary tissue growth factor profile in a randomized trial among women at high-risk of breast cancer (i.e., cytological confirmed atypia); and Aim 3 (mechanistic): Identification and validation of growth factor and signaling pathway modulation using targeted molecular analyses (IHC, RT-PCR) in combination with unbiased approaches [i.e., Reverse Phase Protein Microarray]. To test the mechanistic role of exercise-induced growth factor withdrawal, we will over express growth factor availability or growth factor receptor activity using genetic (knock-in models) or pharmacological (specific agonistic antibodies) strategies. This sub-aim will be addressed using in vitro experiments using human premalignant cell lines exposed to serum from patient samples obtained in Aim 2 as well recombinant growth factors using 'add back' experiments.