Growth Hormones and Breast Cancer Risk

摘要 生长因子与乳腺癌病因学之间的关系是复杂的，尚未完全了解; 然而，强有力的实验证据支持它们在乳腺癌发生中的作用。所以在这 根据这项建议，我们将对催乳素及其与乳腺癌风险的关系进行详细评估。这 研究将采用前瞻性巢式病例对照设计，在绝经前或围绝经期妇女中， 收集（截至2011年确诊的1 542例）。样本是在护士健康研究II中收集的 1996- 1999年从29,611名年龄在32至52岁之间的妇女中，以及1989- 1990年从32,826名国民保健服务参与者中， 43至62岁。除了评估催乳素与乳腺癌的整体关联外，这项研究还将 检查催乳素是否与雌激素受体阳性肿瘤的风险更密切相关， 因为肿瘤对催乳素、催乳素受体、细胞周期蛋白D1和磷酸化STAT 3和STAT 5染色呈阳性。 观察到这种对催乳素受体及其下游靶点的特异性将大大增加催乳素受体及其下游靶点的特异性。 因果关系。先前的研究使用免疫测定法评估催乳素水平， 具有不同生物活性的同种型。这项研究将提供第一个前瞻性评估乳腺癌 用催乳素生物活性测定来评估癌症风险，这可能更好地反映了催乳素的生物活性部分。 重要.此外，由于已知的生物活性催乳素的相关性很少，因此本提案将首先评估 时间，其与已知和推定的乳腺癌风险因素的关系（例如，奇偶校验，轮班工作）。的可用性 这一队列的现有激素数据将使催乳素作为一个独立的乳腺癌检查成为可能。 癌症风险因素及其与其他激素的相互关系。重要的是，我们增加了一个目标， 评估将催乳素添加到乳腺癌综合风险预测模型中， 临床上有用。催乳素的几个特征使其成为纳入此类模型的有吸引力的候选者， 包括免疫测定是一种标准化和常见的临床测定， 来衡量。此外，催乳素相关性的大小似乎与其他因素相似， 在乳腺癌风险预测模型中。我们还将评估生物测定的纳入情况;如果情况有所改善， 预测优于免疫测定，这将为确定催乳素的特定亚型提供动力 这增加了患乳腺癌的风险，并开发了廉价的检测方法。其他赠款将 为后续和其他激素检测提供资金，提高该项目的成本效益。 最终，阐明催乳素在乳腺癌中的作用可以为乳腺癌的研究开辟多个新的领域。 治疗和预防。

ABSTRACT The relationship between growth factors and breast cancer etiology is complex and not completely understood; however, strong experimental evidence supports their role in breast carcinogenesis. Therefore, in this proposal, we will conduct a detailed evaluation of prolactin and its association with breast cancer risk. This study will use a prospective nested case-control design among pre- or perimenopausal women at blood collection (1,542 cases diagnosed through 2011). Samples were collected in the Nurses' Health Study II (NHSII) in 1996-99 from 29,611 women, ages 32 to 52 years, and in 1989-90 from 32,826 NHS participants, ages 43 to 62 years. In addition to assessing the overall prolactin-breast cancer association, this study will examine whether prolactin is more strongly associated with risk of estrogen receptor positive tumors, as well as tumors staining positive for prolactin, prolactin receptor, cyclin D1, and phosphorylated STAT3 and STAT5. Observing such specificity to the prolactin receptor and its downstream targets would add substantially to the case for causality. Prior studies have assessed prolactin levels using an immunoassay that measures multiple isoforms with differing biologic activities. This study will provide the first prospective assessment of breast cancer risk with a prolactin bioactivity assay, which may better reflect the portion of prolactin that is biologically important. Also, since few correlates of bioactive prolactin are known, this proposal will assess, for the first time, its relationship with known and putative breast cancer risk factors (e.g., parity, shift work). The availability of existing hormone data for this cohort will enable the examination of prolactin as an independent breast cancer risk factor and its interrelationships with other hormones. Importantly, we have added an aim to directly evaluate the addition of prolactin to a comprehensive risk prediction model for breast cancer, which could be useful clinically. Several features of prolactin make it an attractive candidate for inclusion into such models, including that the immunoassay is a standardized and common clinical assay that is very inexpensive and easy to measure. Further, the magnitude of the prolactin association appears to be similar to other factors included in breast cancer risk prediction models. We also will evaluate the inclusion of the bioassay; if this improves prediction better than the immunoassay, it would provide impetus to identify the specific isoforms of prolactin that increase risk of breast cancer and develop inexpensive assays for their measurement. Other grants will provide funding for follow-up and other hormone assays, increasing the cost-effectiveness of this project. Ultimately, elucidating the role of prolactin in breast cancer could open up multiple new areas of research for both treatment and prevention.