Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Breast Cancer Res Treat. 2017 Nov;166(1):133-143. doi: 10.1007/s10549-017-4413-3. Epub 2017 Jul 27.
Breast terminal duct lobular units undergo two distinctive physiological processes of involution: age-related lobular involution (LI), which is gradual and associated with decreased breast cancer risk, and postlactational involution, which is relatively precipitous, occurs with weaning, and has been associated with potentiation of tumor aggressiveness in animal models. Here we assessed whether markers of postlactational involution are associated with ongoing LI in a retrospective tissue cohort.
We selected 57 women from the Mayo Clinic Benign Breast Disease Cohort who underwent multiple biopsies and who were average age 48 at initial biopsy. Women were classified as having progressive or non-progressive LI between initial and subsequent biopsy. Serial tissue sections were immunostained for plasminogen, matrix metalloproteinase 9 (MMP-9), phospho-STAT3 (pSTAT3), tenascin C, Ki67, CD44, cytokeratin 14 (CK14), cytokeratin 19 (CK19), and c-myc. All but Ki67 were digitally quantified. Associations between maximal marker expression per sample and progressive versus non-progressive LI were assessed using logistic regression and adjusted for potential confounders.
While no biomarker showed statistically significant association with LI progression when evaluated individually, lower expression of pSTAT3 (OR 0.35, 95% CI 0.13-0.82, p = 0.01) and higher expression of plasminogen (OR 2.89, 95% CI 1.14-8.81, p = 0.02) were associated with progressive LI in models simultaneously adjusted for all biomarkers. Sensitivity analyses indicated that the strengthening in association for pSTAT3 and plasminogen with progressive LI was due to collinearity between these two markers.
This is the first study to identify biomarkers of active LI. Our findings that plasminogen and pSTAT3 are significantly associated with LI suggest that they may represent signaling nodes or biomarkers of pathways common to the processes of postlactational involution and LI.
乳腺终末导管小叶单位经历两种不同的退化生理过程：与乳腺癌风险降低相关的年龄相关小叶退化（LI）和哺乳期后退化，后者相对突然，发生在断奶时，并已在动物模型中与肿瘤侵袭性的增强有关。在这里，我们评估了产后退化的标志物是否与回顾性组织队列中的持续 LI 相关。
我们从梅奥诊所良性乳腺疾病队列中选择了 57 名接受多次活检且初次活检时平均年龄为 48 岁的女性。根据初次和后续活检之间 LI 是否进展，将女性分为进展性或非进展性 LI。对连续组织切片进行纤溶酶原、基质金属蛋白酶 9（MMP-9）、磷酸化 STAT3（pSTAT3）、腱糖蛋白 C、Ki67、CD44、细胞角蛋白 14（CK14）、细胞角蛋白 19（CK19）和 c-myc 的免疫染色。除 Ki67 外，所有标志物均进行了数字化定量。使用逻辑回归评估每个样本中最大标志物表达与进展性 LI 与非进展性 LI 之间的相关性，并根据潜在混杂因素进行调整。
虽然在单独评估时，没有一种生物标志物与 LI 进展有统计学显著关联，但 pSTAT3 表达降低（OR 0.35，95%CI 0.13-0.82，p=0.01）和纤溶酶原表达升高（OR 2.89，95%CI 1.14-8.81，p=0.02）与所有标志物同时调整的模型中，与进展性 LI 相关。敏感性分析表明，pSTAT3 和纤溶酶原与进展性 LI 的关联增强是由于这两个标志物之间的共线性。
这是第一项鉴定活跃 LI 生物标志物的研究。我们的研究结果表明，纤溶酶原和 pSTAT3 与 LI 显著相关，这表明它们可能代表哺乳期后退化和 LI 过程中的信号节点或共同途径的生物标志物。
