Growth Hormones and Breast Cancer Risk

摘要 生长因子与乳腺癌病因的关系复杂，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。因此，在这个 我们将对催乳素及其与乳腺癌风险的关系进行详细的评估。这 研究将在绝经前或围绝经期妇女中使用前瞻性嵌套病例对照设计 收集(2011年确诊1,542例)。样本收集于《护士健康研究II》 (NHSII)1996-1999年从29,611名年龄在32岁至52岁的妇女，以及1989-90年从32,826名NHS参与者， 年龄在43岁到62岁之间。除了评估整个催乳素与乳腺癌的关系外，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有更强的相关性 催乳素、催乳素受体、细胞周期蛋白D1、磷酸化STAT3和STAT5阳性的肿瘤。 观察催乳素受体及其下游靶点的这种特异性将大大增加 因果关系的理由。以前的研究已经使用一种免疫测定法来评估催乳素水平，该方法测量了 具有不同生物活性的异构体。这项研究将首次对乳房进行前瞻性评估。 催乳素生物活性测定的癌症风险，这可能更好地反映催乳素在生物学上的部分 很重要。此外，由于鲜为人知的生物活性催乳素的相关性，这项提案将首次评估 时间，它与已知和推测的乳腺癌风险因素(例如，产次、轮班工作)的关系。可得性 这一队列的现有激素数据将使催乳素作为一个独立的乳房进行检查 癌症危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，直接 评估将催乳素添加到乳腺癌综合风险预测模型中，这可能是 在临床上很有用。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， 包括免疫分析是一种标准化和常见的临床检测方法，非常便宜和容易 来衡量。此外，催乳素相关性的大小似乎与包括的其他因素相似 在乳腺癌风险预测模型中。我们还将评估生物检测的包容性；如果这一点有所改善 比免疫分析更好的预测，它将为鉴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来测量它们。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能会开辟多个新的研究领域 治疗和预防并重。

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.