Abstract 2324: Associations of circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 with the expression of stromal markers in women with benign breast tissue

Abstract Purpose: The breast tissue microenvironment, and specifically stroma, is important for maintaining the normal tissue structure, and alterations within this environment may influence breast cancer (BCa) risk. The resident (normal) fibroblasts are the most abundant stromal cells. In breast tumors, cancer-associated fibroblasts have been associated with more aggressive phenotypes, and resistance to treatment. The insulin-like growth factor (IGF) pathway is involved in breast epithelial cell growth and extracellular matrix remodeling and may potentially influence normal fibroblasts. To date this association has not been explored in epidemiological studies. We examined, for the first time, the associations of circulating IGF-1 and IGF binding protein-3 (IGFBP-3) with the expression of breast stromal markers related to fibroblast activation: alpha-smooth muscle actin (αSMA), tenascin-C (TNC), fibroblast activation protein (FAP), calcyclin (s100a6), and matrix metallo-peptidase (MMP14). Methods: This study included 145 cancer-free women with incident biopsy-confirmed benign breast disease (BBD) from the Nurses’ Health Study II (NHSII) cohort. The data on BCa risk factors were obtained from biennial questionnaires. Immunofluorescence (IF) of stromal markers was performed on tissue microarrays with commercial antibodies (αSMA: 1:400 dilution; FAP: 1:50; MMP14: 1:150; TNC: 1:200; s100a6: 1:300). For each core, the % positivity was quantified by inForm v2.6.0. Generalized linear regression was used to examine the associations of plasma IGF-1 and IGFBP-3 (continuous log-transformed and quartiles) with log-transformed positivity for each stromal marker, adjusted for BCa risk factors and BBD subtype. Results: In multivariate analysis, circulating IGF-1 was positively associated with s100a6 expression both when modeled continuously (β=0.89, 95% 95% Confidence Interval [CI] 0.07, 1.71) and as quartiles (β for 4th vs. 1st quartile=0.82, CI 0.16, 1.48; p-trend=0.03). Women whose circulating IGFBP-3 levels were in the top quartile appeared to have lower expression of TNC (β=-2.51, 95% CI -4.75, -0.27; p-trend=0.08). No associations were seen for αSMA, FAP, and MMP14. Conclusion: Our findings suggest positive associations of circulating IGF-1 with s100a6 and inverse associations of IGFBP-3 with TNC, consistent with previously reported positive associations of IGF-1 and inverse associations of IGFBP-3 with BCa risk. Future studies are warranted to confirm our findings. Citation Format: Lusine Yaghjyan, Yu Jing J. Heng, Brian R. Sardella, Maisey Ratcliffe, Rulla M. Tamimi. Associations of circulating insulin-like growth factor-1 and insulin-like growth factor binding protein-3 with the expression of stromal markers in women with benign breast tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2324.