The Role of Prolactin in the Etiology of Postmenopausal Breast Cancer

催乳素在绝经后乳腺癌病因学中的作用

• 批准号: 7367881
• 负责人: Shelley S Tworoger
• 金额: $ 19.37万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367881
• 关键词: Address; Affect; Age; Alcohol consumption; Animals; Archives; Biological Assay; Biological Markers; Blood; Blood specimen; Body Size; Body mass index; Breast; Breast Cancer Risk Factor; Cancer Etiology; Case-Control Studies; Cell Proliferation; Cell Survival; Collection; DNA; Data; Development; Diet; Disease; Estrogen Receptors; Estrogen receptor positive; Estrogens; Etiology; Exons; Family history of; First Births; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Grant; Haplotypes; High birth weight infant; Hip region structure; In Vitro; Invasive; Lactation; Lead; Leukocytes; Life; Life Style; Mammary Neoplasms; Measures; Nulliparity; Nurses' Health Study; Paraffin Embedding; Participant; Persons; Physical activity; Pilot Projects; Plasma; Population; Postmenopause; Pregnancy; Progesterone Receptors; Prolactin; Prolactin Receptor; Public Health; Questionnaires; Receptor Gene; Recording of previous events; Regulation; Reproductive History; Risk; Role; Sampling; Single Nucleotide Polymorphism; Staining method; Stains; Testing; Tissue Banks; Tissue Sample; Tumor Tissue; Vascularization; Woman; Work; animal data; base; cancer risk; cell motility; early childhood; energy balance; improved; malignant breast neoplasm; prevent; progesterone receptor positive; prolactin-binding protein; promoter; prospective; receptor; tumor; tumorigenesis

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.

我们建议评估几种假设，以研究催乳素在绝经后乳腺癌病因中的作用，这些假设基于我们先前的发现，即催乳素水平与侵入性绝经后乳腺癌的风险正相关，其雌激素受体阳性肿瘤的风险特别增加。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育中的作用，特别是通过促进细胞增殖，增加细胞存活，改变细胞运动性并支持肿瘤血管化。分析将使用护士健康研究的数据进行，该研究始于1976年，使用1989 - 1990年提供血液样本的妇女（约33,000），还专注于乳腺癌病例的一部分（约500例），他们既有血液样本又有肿瘤组织块。具体而言，使用从白细胞获得的生殖线DNA，我们将通过研究遗传变异性在血液和乳腺癌风险中的催乳素浓度在血液和乳腺癌风险中的作用来扩展我们的发现。我们还将提供首次分析，研究乳腺肿瘤中催乳素受体状态是否会使用我们独特的基于人群的组织库修饰催乳素浓度与乳腺癌风险之间的关联。此外，我们建议扩大有关催乳素水平与各种生活方式与其他乳腺癌危险因素之间关系的信息，尤其是专注于生殖因素，能量平衡和饮食，早期生活暴露和乳腺癌家族史。这些分析将有助于我们更好地了解血浆中催乳素水平的调节，并提供有关这些因素如何改变乳腺癌风险的潜在机械信息。最后，我们建议对两种测定法进行重要和必要的试点测试，这些测定方法将提供未来赠款中将其作为生物标志物的初步数据。该应用的主要优势是乳腺癌病例的前瞻性收集以及问卷数据的可用性，存档的血浆和DNA样品以及我们乳腺癌病例的肿瘤组织样本。提出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发展的理解来影响公共卫生，这反过来又可以更好地了解如何预防这种疾病。