Nipple Fluid Hormone Levels and Breast Cancer Risk

描述（由申请人提供）：终生接触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，针对内分泌轴的预防策略的风险-效益比将显著提高。乳头液激素水平是乳腺癌风险的有吸引力的候选标记物。我们的初步研究提供了初步数据，乳头抽吸液（NAF）中的性类固醇（雌二醇和孕酮）水平是绝经前和绝经后妇女乳腺癌风险的潜在生物标志物。我们发现，这些标记物在NAF中的含量明显高于血清，随着时间的推移保持稳定，并且具有生物学相关性，这反映在NAF雌二醇水平与NAF中雌激素反应蛋白含量的强相关性上。此外，我们表明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，并且在停止口服避孕药后上升。最后，初步分析首次表明，NAF雌二醇和孕酮与估计的Gail风险之间存在相关性。本提案要检验的主要假设是NAF雌二醇水平是激素敏感性乳腺癌风险的标志。为了实现这一目标，我们建议对600名妇女进行病例对照研究：300名新诊断的40至60岁的乳腺癌患者来自Lynn Sage乳腺中心，300名来自邻近的西北大学乳房x光检查中心。病例和对照组将根据年龄和绝经状态进行匹配。我们将获得NAF、血液样本和乳房x线摄影密度测量。NAF检测将包括性类固醇（雌二醇和孕酮）、它们的前体（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）。我们将进行亚分析，以检验特定乳腺癌危险因素、绝经状态和种族对NAF激素与乳腺癌风险之间关系的影响。我们将通过检测雌激素和黄体酮相关蛋白的NAF含量来寻找NAF激素水平的生物学重要性的确凿证据。通过检查病例中癌症的激素受体（HR）状态，我们将验证NAF激素水平与HR阳性乳腺癌的相关性更强的假设。最后，我们将评估NAF激素在病例和对照组中解释乳房x线摄影密度的程度。该项目通过评估乳腺内、乳房x线摄影密度和癌症风险，将为NAF激素作为新的乳腺癌风险标志物的有效性提供数据，这些标志物可以通过预防性干预来调节，因此可以作为评估其效果的替代终点。

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.