Abstract
PurposeBreast 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.MethodsWe 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.ResultsWhile 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.ConclusionsThis 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.
Highlights
Terminal duct lobular units (TDLUs) are microscopic structures comprising terminal ducts and acinar substructures that produce milk after birth and may develop cancerBreast Cancer Res Treat (2017) 166:133–143 precursors among some women
While no biomarker showed statistically significant association with lobular involution (LI) progression when evaluated individually, lower expression of pSTAT3 and higher expression of plasminogen 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
Summary
Terminal duct lobular units (TDLUs) are microscopic structures comprising terminal ducts and acinar substructures that produce milk after birth and may develop cancerBreast Cancer Res Treat (2017) 166:133–143 precursors among some women. Analysis of the Mayo Clinic Benign Breast Disease (BBD) cohort of more than 13,000 women who underwent a surgical biopsy diagnosed as BBD showed that the timing of LI centers around the perimenopausal years, there was considerable variation among women [2], and that incomplete LI among postmenopausal women or delays in the ongoing process of LI are associated with increased breast cancer (BC) risk [2, 3]. Such observations indicate that investigations to understand the biological processes underlying LI may reveal markers and mechanisms associated with lowering of breast cancer risk. Experimental studies using animal models have shown that delays in postlactational lobular involution are associated with increased cancer incidence and progression [13]
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