The Role of Prolactin in the Etiology of Postmenopausal Breast Cancer

我们建议评估几个检验催乳素在绝经后乳腺癌病因中的作用的假说，这些假说建立在我们之前的发现基础上，即催乳素水平与浸润性绝经后乳腺癌的风险正相关，尤其是雌激素受体阳性肿瘤的风险增加。大量的体外和动物数据支持催乳素和催乳素受体在乳腺癌发展中的作用，特别是通过促进细胞增殖、增加细胞存活率、改变细胞运动和支持肿瘤血管形成。分析将使用始于1976年的护士健康研究的数据，使用的是1989-1990年间提供血液样本的妇女(约33,000人)，还将重点放在我们既有血液样本又有肿瘤组织块的乳腺癌病例子集(约500人)上。具体地说，我们将通过使用从白细胞中获得的生殖系DNA来研究遗传变异性与血液中催乳素浓度和乳腺癌风险之间的作用，从而扩展我们的发现。我们还将利用我们独特的基于人群的组织库，首次分析乳腺肿瘤中催乳素受体状态是否会改变催乳素浓度和乳腺癌风险之间的关联。此外，我们建议扩大关于催乳素水平与各种生活方式和其他乳腺癌危险因素的关系的信息，特别是关注生殖因素、能量平衡和饮食的衡量标准、早期生活暴露以及乳腺癌家族史。这些分析将帮助我们更好地了解血浆中催乳素水平的调节，并提供关于这些因素如何改变乳腺癌风险的潜在机制信息。最后，我们建议对两种化验进行重要和必要的中试测试，这两种化验将提供必要的初步数据，以便在未来的拨款中将这些作为生物标记物进行研究。这一应用程序的主要优势是可以预期收集乳腺癌病例，并可获得调查问卷数据、存档的血浆和DNA样本以及乳腺癌病例的肿瘤组织样本。拟议的分析将提高我们对催乳素和催乳素受体在绝经后乳腺癌病因中的作用的理解。这可能会通过增加我们对乳腺癌如何发展的了解来潜在地影响公众健康，这反过来可以导致对如何预防这种疾病的更好理解。

We propose to evaluate several hypotheses examining the role of prolactin in postmenopausal breast cancer etiology, which build upon our previous findings that prolactin levels are positively associated with risk of invasive postmenopausal breast cancer, with a particularly increased risk for estrogen receptor positive tumors. Substantial in vitro and animal data support the role of prolactin and the prolactin receptor in breast cancer development, specifically by promoting cell proliferation, increasing cell survival, altering cellular motility, and supporting tumor vascularization. Analyses will be conducted using data from the Nurses' Health Study, which began in 1976, using women who provided a blood sample in 1989-1990 (approximately 33,000) and also focusing on a subset of breast cancer cases (approximately 500) for whom we have both a blood sample and tumor tissue blocks. Specifically we will extend our findings by examining the role of genetic variability with respect to both prolactin concentrations in the blood and breast cancer risk, using germline DNA obtained from white blood cells. We will also provide the first analysis examining whether prolactin receptor status in breast tumors modifies the association between prolactin concentrations and breast cancer risk, using our unique population-based tissue bank. In addition, we propose to expand information concerning the relationship between prolactin levels and various lifestyle and other breast cancer risk factors, particularly focusing on reproductive factors, measures of energy balance and diet, early life exposures, and family history of breast cancer. These analyses will help us to better understand the regulation of prolactin levels in plasma as well as provide potential mechanistic information on how these factors may modify risk of breast cancer. Finally we propose to conduct important and necessary pilot testing for two assays that will provide preliminary data needed to pursue these as biomarkers in a future grant. Major strengths of this application are the prospective collection of breast cancer cases and the availability of questionnaire data, archived plasma and DNA samples, and tumor tissue samples from our breast cancer cases. The proposed analyses will improve our understanding of the role of prolactin and the prolactin receptor in postmenopausal breast cancer etiology. This potentially may affect public health by increasing our understanding of how breast cancer develops, which in turn can lead to a better understanding of how to prevent this disease.