Nipple Fluid Hormone Levels and Breast Cancer Risk

描述（由申请人提供）：终生暴露于性类固醇是乳腺癌风险的主要因素。如果能够评估激素敏感性乳腺癌的风险，那么针对内分泌轴的预防策略的风险效益比将得到显著改善。乳头液激素水平是乳腺癌风险的有吸引力的候选标志物。我们的试点研究提供了初步数据，乳头抽吸液（NAF）水平的性类固醇（雌二醇和孕酮）是潜在的生物标志物的乳腺癌风险在绝经前和绝经后妇女。我们发现，这些标志物显着高于NAF在血清中，是稳定的，随着时间的推移，是生物相关的，反映了NAF雌二醇水平与NAF中雌激素反应蛋白的含量的强相关性。此外，我们发现NAF的激素含量反映了全身环境，因为激素水平随着激素替代疗法的使用而升高，口服避孕药使用者的激素水平较低，停止口服避孕药后激素水平升高。最后，初步分析首次显示NAF雌二醇和孕酮与估计的盖尔风险相关。在这项建议中要检查的主要假设是，NAF雌二醇水平是激素敏感性乳腺癌风险的标志物。为了实现这一目标，我们提出了一个病例对照研究600名妇女：300名新诊断的乳腺癌病例，年龄在40至60岁的林恩塞奇乳腺中心，和300名对照，从邻近的乳房X线检查筛查中心的西北。病例和对照组将在年龄和绝经状态方面进行匹配。我们将获得NAF、血液样本和乳房X线摄影密度测量结果。NAF检测将包括性类固醇（雌二醇和孕酮）、其前体（雌酮、硫酸雌酮、雄烯二酮脱氢表雄酮和睾酮）和相关蛋白（表皮生长因子、组织蛋白酶D、pS2和前列腺特异性抗原）。我们将进行亚组分析，以检查特定乳腺癌风险因素、绝经状态和种族对NAF激素和乳腺癌风险之间关系的影响。我们将通过检测雌激素和孕激素相关蛋白的NAF含量来寻求NAF激素水平的生物学重要性的确证证据。通过检查病例中癌症的激素受体（HR）状态，我们将检验NAF激素水平与HR阳性乳腺癌更密切相关的假设。最后，我们将评估NAF激素在多大程度上解释病例和对照组的乳腺摄影密度。该项目评估了乳腺内分泌学、乳腺摄影密度和癌症风险，将提供关于NAF激素作为新的乳腺癌风险标志物的有效性的数据，这些标志物可能通过预防性干预措施进行调节，因此可以作为替代终点来评估其影响。

DESCRIPTION (provided by applicant): Lifetime exposure to sex steroids is a major contributor to breast cancer risk. The risk-benefit ratio of prevention strategies that target the endocrine axis would be significantly improved if it were possible to assess risk for hormone sensitive breast cancer. Nipple fluid hormone levels are attractive candidate markers of breast cancer risk. Our pilot studies provide preliminary data that nipple aspirate fluid (NAF) levels of sex steroids (estradiol and progesterone) are potential biomarkers of breast cancer risk in both pre and postmenopausal women. We show that these markers are significantly higher in NAF than in serum, are stable over time, and are biologically relevant, as reflected by the strong correlations of NAF estradiol levels with the content of estrogen response proteins in NAF. Additionally, we show that the hormone content of NAF reflects the systemic environment, since hormone levels rise with the use of hormone replacement therapy, are low in oral contraceptive users, and rise after cessation of oral contraceptives. Finally, preliminary analyses show, for the first time, a correlation of NAF estradiol and progesterone with estimated Gail risk. The primary hypothesis to be examined in this proposal is that NAF estradiol levels are markers of risk for hormone sensitive breast cancer. To accomplish this, we are proposing a case-control study of 600 women: 300 newly diagnosed breast cancer cases aged 40 to 60 from the Lynn Sage Breast Center, and 300 controls from the adjacent Mammography Screening Center of Northwestern. Cases and controls will be matched for age and menopausal status. We will obtain NAF, blood samples, and mammographic density measurements. NAF assays will include sex steroids (estradiol and progesterone), their precursors (estrone, estrone sulphate, androstenedione dehydroepiandrosterone and testosterone) and related proteins (epidermal growth factor, cathepsin D, pS2, and prostate specific antigen). We will perform sub-analyses to examine the effect of specific breast cancer risk factors, menopausal status, and race on the association of NAF hormones and breast cancer risk. We will seek corroborating evidence for the biological importance of NAF hormone levels by examining the NAF content of estrogen and progesterone related proteins. By examining the hormone receptor (HR) status of the cancers among cases, we will test the hypothesis that NAF hormone levels are more strongly related to HR positive breast cancers. Finally, we will assess the degree to which NAF hormones explain mammographic density in cases and controls. This project, evaluating breast intracrinology, mammographic density, and cancer risk will provide data on the validity of NAF hormones as new breast cancer risk markers, which can potentially be modulated by preventive interventions and therefore may serve as surrogate endpoints to assess their effects.