Associations of stromal markers with breast terminal duct lobular involution

Background: Elevated expression of stromal markers in breast cancer (BrCa) has been linked to more aggressive disease and poorer prognosis. In contrast, data on stromal marker expression in premalignant breast tissues are limited, and it remains unclear whether these markers may inform future BrCa risk. Terminal duct lobular involution (TDLU), a physiologic process characterized by a decreased number of TDLUs and acini within breast lobules, has been associated with lower BrCa risk and is considered a potential surrogate risk marker for BrCa. In this study, we examined the associations between five stromal markers and TDLU involution in premalignant breast tissues. Design: Tissue microarrays from 260 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII were stained and evaluated for alpha-smooth muscle actin (alphaSMA), fibroblast activation protein (FAP), matrix metallo-peptidase (MMP14), tenascin-C (TNC), and calcyclin (s100A6). For each core, the % positivity was quantified by the inForm software. Our previously published computational algorithm computed six measures of TDLU involution assessing the number of TDLUs (TDLU counts/non-adipose tissue area), TDLU size (median TDLU span, median TDLU area, and TDLU area/% of non-adipose tissue area), and TDLU development (median acini counts/TDLU and median acini density). The associations of each marker's expression (binary with 1% cut-off) with each feature (log-transformed) was examined using generalized linear regression, adjusting for established BCa risk factors. Results: The expression of alphaSMA and MMP14 was positively associated with four out of five features related to TDLU size and development (all p <0.05). FAP expression was positively associated with three features of TDLU size and development: median TDLU span, median TDLU area, and median acini counts/TDLU (all p <0.05). TNC expression was positively associated with median TDLU span but inversely associated with median acini density and TDLU counts/non-adipose tissue area (all p <0.05). No associations were found for s1006a. Conclusions: The expression of several stromal markers in benign breast tissue was associated with larger TDLUs and more acini, i.e., lower degrees of lobular involution. Studies are underway to evaluate if these findings translate into associations with increased BCa risk.