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

描述（由申请人提供）：乳腺癌是美国女性中最常见的恶性肿瘤，预计2012年约有229,000例新诊断和约39,000例死亡。此外，预计今后20年乳腺癌发病率将增加约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，但在医学上，它在高达30%的高危女性中是相矛盾的，与几种不良毒性相关，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，在绝经前和绝经后妇女中，定期运动与ER+和ER-乳腺癌发病率降低20%-30%始终相关。然而，强调这种关联的宿主和/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，本基金的目的是在临床前和临床研究中阐明运动对乳腺癌起始抑制的“剂量-反应”效应，以及生长因子戒断对这种效应的调节作用。我们的中心假设是，以剂量依赖的方式，运动将减少宿主（外周循环）和乳腺组织中促炎生长因子的可用性，进而有效抑制诱导向恶性表型转变的“核心”细胞信号通路。这一中心假设将通过跨越实验室到临床研究的三个转化目标来解决。目的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”；目的2（临床）：在一项随机试验中，确定运动训练对乳腺癌高危女性（即细胞学证实的非典型型）乳腺组织生长因子谱的“剂量反应”；目标3（机制）：使用靶向分子分析（IHC, RT-PCR）结合无偏方法（即逆相蛋白质微阵列）鉴定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戒断的机制作用，我们将使用基因（敲入模型）或药理学（特异性激动抗体）策略过度表达生长因子可用性或生长因子受体活性。这一子目标将通过体外实验来解决，该实验使用的是暴露于目标2中获得的患者样本血清中的人癌前细胞系，以及使用“加回”实验来重组生长因子。

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.