Gann Peter H, Geiger Angela S, Helenowski Irene B, Vonesh Edward F, Chatterton Robert T
Department of Preventive Medicine, The Robert Lurie Comprehensive Cancer Center, Feinberg Medical School, Northwestern University, Chicago, IL 60612, USA.
Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):39-44. doi: 10.1158/1055-9965.EPI-05-0470.
Concentrations of estrogen and progesterone within the breast could provide a better reflection of breast cancer risk than levels in the circulation. We developed highly sensitive immunoassays for multiple steroid hormones and proteins in the nipple aspirate fluid (NAF), which can be obtained noninvasively with a simple suction device. Previous studies showed that NAF hormone levels are strongly correlated between breasts and within a single breast over time and are predictably related to hormone replacement therapy or use of oral contraceptives. This study evaluates the relationship of NAF estrogen and progesterone levels to those in serum and saliva, the relationship of NAF estradiol to androgenic and estrogenic precursors in NAF, and the relationship of NAF hormone levels to those of response proteins such as cathepsin D and epidermal growth factor (EGF).
Normal premenopausal women collected saliva daily and donated blood and NAF in the midluteal phases of menstrual cycles at intervals of 0, 4, 12, and 15 months. Analytes were measured by immunoassays after solvent fractionation. Log-transformed values were fit to repeated measures analysis of covariance models to ascertain associations between analytes.
Small nonsignificant associations were found between NAF and serum or salivary estradiol. However, progesterone in NAF was significantly associated with progesterone in serum and saliva (R=0.18 and 0.32, respectively). Within NAF, the estradiol precursors estrone sulfate, androstenedione, and dehydroepiandrosterone were significantly associated with estradiol concentration (P<0.06), and a multiprecursor model explained the majority of variance in NAF estradiol (model R(2)=0.83). Cathepsin D and EGF in NAF could not be predicted from serum or salivary steroid measurements; however, both could be predicted from estradiol and its precursors in NAF (model R(2)=0.70 and 0.93, respectively).
By showing consistent associations between estradiol and its precursors and response proteins, these data provide support for the biological validity of NAF hormone measurements and for the importance of steroid interconversion by aromatase and sulfatase within the breast. The low correlation between estrogen levels in NAF and those in serum or saliva suggests that the degree of association between estrogen or its androgen precursor levels and risk of breast cancer observed in epidemiologic studies using serum estimates might be highly attenuated.
乳腺内雌激素和孕酮的浓度可能比循环中的水平更能反映乳腺癌风险。我们开发了用于乳头抽吸液（NAF）中多种甾体激素和蛋白质的高灵敏度免疫测定法，NAF可通过简单的抽吸装置无创获取。先前的研究表明，NAF激素水平在双侧乳房之间以及同一乳房内随时间具有很强的相关性，并且与激素替代疗法或口服避孕药的使用有可预测的关系。本研究评估了NAF中雌激素和孕酮水平与血清及唾液中相应激素水平的关系、NAF中雌二醇与雄激素和雌激素前体的关系，以及NAF激素水平与组织蛋白酶D和表皮生长因子（EGF）等反应蛋白水平的关系。
正常绝经前女性每天收集唾液，并在月经周期的黄体中期，分别于0、4、12和15个月时捐献血液和NAF。经溶剂分级分离后，通过免疫测定法测量分析物。对经对数转换的值进行重复测量协方差模型分析，以确定分析物之间的关联。
NAF与血清或唾液中的雌二醇之间存在微小的无显著意义的关联。然而，NAF中的孕酮与血清和唾液中的孕酮显著相关（相关系数分别为0.18和0.32）。在NAF中，雌二醇前体硫酸雌酮、雄烯二酮和脱氢表雄酮与雌二醇浓度显著相关（P<0.06），一个多前体模型解释了NAF中雌二醇的大部分变异（模型决定系数R²=0.83）。无法根据血清或唾液中的甾体测量值预测NAF中的组织蛋白酶D和EGF；然而，两者均可根据NAF中的雌二醇及其前体进行预测（模型决定系数分别为0.70和0.93）。
这些数据通过显示雌二醇及其前体与反应蛋白之间的一致关联，为NAF激素测量的生物学有效性以及乳腺内芳香化酶和硫酸酯酶进行的甾体转化的重要性提供了支持。NAF中雌激素水平与血清或唾液中雌激素水平之间的低相关性表明，在使用血清估计值的流行病学研究中观察到的雌激素或其雄激素前体水平与乳腺癌风险之间的关联程度可能会大大减弱。
