Assessing the role of androgens in breast cancer risk

评估雄激素在乳腺癌风险中的作用

• 批准号: 8692673
• 负责人: Susan E Hankinson
• 金额: $ 41.68万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692673
• 关键词: Accounting; Address; Age; Age at Menarche; Alcohol consumption; Androgen Antagonists; Androgen Receptor; Androgens; Antiandrogen Therapy; Bilateral oophorectomy; Biological Models; Blood specimen; Breast; Breast Cancer Risk Factor; Breast Carcinogenesis; Breast Epithelial Cells; Cancer Etiology; Chemoprevention; Cohort Studies; Data; Dehydroepiandrosterone Sulfate; Development; Energy Metabolism; Epidemiology; Epithelial; Estrogen Receptor Status; Estrogen Receptors; Estrogens; Evaluation; FDA approved; Funding; Genes; Genetic Transcription; High Risk Woman; Immunohistochemistry; Joints; Label; Laboratories; Life Style; Link; Malignant - descriptor; Mammary Neoplasms; Menopause; Nurses' Health Study; Ovariectomy; Pathway interactions; Pharmaceutical Preparations; Physical activity; Plasma; Play; Postmenopause; Prospective Studies; Public Health; Questionnaires; Raloxifene; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Tamoxifen; Testosterone; Testosterone Sulfate; Tumor Markers; Tumor Subtype; Tumor Tissue; Waist-Hip Ratio; Water; Woman; cancer chemoprevention; cancer risk; cohort; energy balance; epidemiologic data; high risk; insight; malignant breast neoplasm; novel; prospective; protein expression; receptor; receptor expression; response; tumor; validation studies

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.

说明(由申请者提供)：雌激素在乳腺癌风险中起着关键作用。雄激素在乳腺癌病因学中的作用也被假设，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：高睾酮和DHEAS水平一直与风险增加相关，外源性雌激素和睾酮可能会增加风险，几个已确定的乳腺癌危险因素似乎会改变雄激素环境。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腺肿瘤组织中雄激素局部转化为雌激素的间接影响尚不清楚；我们建议在当前的应用中解决这一问题。此外，体力活动和能量平衡与循环雄激素水平的关系没有被很好地描绘出来，因此我们提出了几项分析，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)的表达以及新的雄激素信号信号在乳腺肿瘤中的表达，更好地确定雄激素在乳腺癌病因中的作用。我们将利用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。有调查问卷数据和肿瘤组织免疫组织化学(IHC)的6,800名患者；其中1,151名绝经后患者(和年龄匹配的对照组)也有血浆睾酮和脱氢表雄酮硫酸盐(DHEAS)水平。对于乳腺癌的一个子集(n=2000)，我们还将利用AR反应基因子集的RNA表达水平来开发一个肿瘤“雄激素信号”，它应该是一个比简单的AR蛋白表达更好的肿瘤雄激素信号标志。具体地说，我们将评估：(1)在AR阳性(与AR阴性)或雄激素特征高(与低)的肿瘤患者中，循环睾酮和DHEAS水平与乳腺癌风险的正相关性是否更强；(2)酒精摄入量和腰臀比与乳腺癌风险的正相关性，以及体力活动和双侧卵巢切除术与风险的负关联，在AR阳性(与AR阴性)或雄激素特征高(与低)的肿瘤女性中是否更强。在这些分析中，我们将考虑雌激素受体状态和雌激素途径信号，以评估这两个途径的独立影响。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联，我们将利用目前由NHS和NHSII队列资助的验证性研究(生活方式验证研究)收集的独特详细的体力活动和能量消耗数据。