Assessing the role of androgens in breast cancer risk

描述（由申请人提供）：雌激素在乳腺癌风险中起着重要作用。雄激素在乳腺癌病因学中的作用也有假设，但仍未得到证实。雄激素受体（AR）在正常和恶性乳腺上皮细胞中表达，实验室证据表明雄激素对乳腺癌发生的不利或有利影响取决于模型系统。流行病学数据支持雄激素对风险的不利影响：高循环睾酮和DHEAS水平一直与风险增加有关，外源性雌激素加睾酮可能增加风险，一些已确定的乳腺癌风险因素似乎改变了雄激素环境。然而，这些流行病学关联是由于雄激素的直接影响还是通过乳房肿瘤组织中雄激素向雌激素的局部转化而产生的间接影响尚不清楚；我们建议在当前的应用中解决这个问题。此外，体力活动和能量平衡与循环雄激素水平的关系还没有很好地描述，因此我们提出了一些分析，将提供新的见解。我们的目标是通过评估雄激素水平、可能至少部分通过雄激素途径起作用的危险因素、雄激素受体（AR）的表达以及乳腺肿瘤中新的雄激素信号特征，更好地定义雄激素在乳腺癌病因学中的作用。我们将利用从正在进行的护士健康研究（NHS）队列中前瞻性收集的数据和血液样本以及肿瘤组织。有6,800例问卷数据和肿瘤组织用于免疫组化（IHC）；其中，1151例绝经后病例（和年龄匹配的对照组）也有血浆睾酮和硫酸脱氢表雄酮（DHEAS）水平。对于一部分乳腺癌病例（n=2000），我们还将利用AR反应基因子集的RNA表达水平开发肿瘤“雄激素信号”，这应该是肿瘤雄激素信号的更好标记，而不是简单的AR蛋白表达。具体而言，我们将评估是否：(1)循环睾酮和DHEAS水平与乳腺癌风险的正相关在AR阳性（相对于AR阴性）或雄激素特征高（相对于低）的肿瘤女性中更强；(2)酒精摄入量和腰臀比与乳腺癌风险呈正相关，而体育锻炼和双侧卵巢切除术与风险呈负相关。在AR阳性（相对于AR阴性）或具有高（相对于低）雄激素特征的肿瘤女性中更强。在这些分析中，我们将考虑雌激素受体状态和雌激素通路信号，以评估两种途径的独立影响。最后，为了更好地定义体力活动、能量平衡和循环雄激素水平之间的关系，我们将利用目前在NHS和NHSII资助的一项验证研究（生活方式验证研究）中收集的独特详细的体力活动和能量消耗数据。

DESCRIPTION (provided by applicant): Estrogens are well established to play a key role in breast cancer risk. A role for androgens in breast cancer etiology also has been hypothesized but remains unconfirmed. Androgen receptors (AR) are expressed in normal and malignant breast epithelial cells and laboratory evidence suggests either an adverse or beneficial effect of androgens on breast carcinogenesis depending on the model system. Epidemiologic data support an adverse influence of androgens on risk: high circulating testosterone and DHEAS levels have been consistently associated with increased risk, exogenous estrogen plus testosterone may increase risk, and several established breast cancer risk factors appear to alter the androgen milieu. However, whether these epidemiologic associations are due to a direct influence of androgens or an indirect influence through the local conversion of androgens to estrogens in breast tumor tissue is not known; we propose to address this issue in the current application. Further, the associations of physical activity and energy balance with circulating androgen levels are not well delineated, and hence we propose several analyses that will provide new insight. We aim to better define the role of androgens in breast cancer etiology by evaluating androgen levels, risk factors that may operate, at least in part, through an androgen pathway, and expression of androgen receptor (AR) as well as a novel androgen signaling signature in the breast tumors. We will utilize prospectively collected data and blood samples, as well as tumor tissue, from the ongoing Nurses' Health Study (NHS) cohort. 6,800 cases with questionnaire data and tumor tissue for immunohistochemistry (IHC) are available; of these, 1,151 postmenopausal cases (and age-matched controls) also have plasma testosterone and dehydroepiandrosterone sulfate (DHEAS) levels available. For a subset of breast cancer cases (n=2000), we also will develop a tumor "androgen signature" using RNA expression levels of a subset of AR response genes, which should be a better marker of tumor androgen signaling than simply AR protein expression. Specifically, we will evaluate whether: (1) the positive associations of circulating testosterone and DHEAS levels with risk of breast cancer are stronger among women with tumors that are AR positive (vs. AR negative) or that have a high (versus low) androgen signature and (2) the positive associations of alcohol intake and waist:hip ratio with breast cancer risk, as well as the inverse associations of physical activity and bilaterl oophorectomy with risk, are stronger among women with tumors that are AR positive (versus AR negative), or have a high (versus low) androgen signature. In these analyses, we will account for estrogen receptor status and estrogen pathway signaling, to evaluate the independent influence of the two pathways. Finally, to better define the associations between physical activity, energy balance and circulating androgen levels, we will utilize uniquely detaile physical activity and energy expenditure data currently being collected in a validation study (the Lifestyle Validation Study) funded within the NHS and NHSII cohorts. PUBLIC HEALTH RELEVANCE: By incorporating an assessment of androgen pathway activity in the breast tumor, and linking this with established or probable breast cancer risk factors and circulating androgen levels in a large prospective study, we should be able to provide new insight into the etiologic importance of androgens in breast carcinogenesis. If androgens were shown to have a direct effect on breast cancer, this would suggest new opportunities for chemoprevention, and would spur further development of anti-androgen therapies that could be recommended for women at high risk of breast cancer.