Abstract 741: Insulin-like growth factor binding protein-3 (IGFBP-3) enhances obesity-related breast tumorigenesis

Abstract

Abstract Introduction and Aim: Epidemiological studies have shown an association between obesity and poor breast cancer prognosis. We have reported that IGFBP-3 influences both breast cancer growth and adipocyte maturation. This study investigated the role of endogenous IGFBP-3 on the development of obesity and subsequently on breast tumor growth. Methods: Wild-type (WT) C57BL/6 or IGFBP-3 knock-out (BP3KO) mice were fed either a high-fat diet (HFD) or control chow diet for 15 weeks, then injected with the syngeneic mouse breast cancer cell line E0771 in the 4th left mammary gland. When the largest tumor reached 1000 mm3, tissues including the mammary fat pad were excised, formalin-fixed and paraffin-embedded for immunohistochemical analysis. Results and Conclusion: Compared to WT mice, BP3KO mice showed both significantly reduced weight gain and mammary fat pad mass (contralateral to tumor) in response to HFD (p < 0.0001, 1-way ANOVA), despite similar food intake between WT and BP3KO mice on HFD. E0771 tumor weight and volume were overall increased by HFD independent of IGFBP-3 status (p = 0.051), and decreased in BP3KO mice independently of diet (p < 0.001, 2-way ANOVA). Despite differences in tumor volumes and weights, tumors from WT and BP3KO mice did not show differences in either the number of mitotically active (Ki67+) or apoptotic (cleaved caspase-3+) cells. Tumors from BP3KO mice however, showed greater infiltration of CD3+ T-cells compared to WT mice (p = 0.0299, 2-way ANOVA). WT and BP3KO mice showed similar intra-tumoral mean vessel densities (CD31+ area) but differed in terms of the relationship between vessel density and final tumor volume. Increased vessel density was associated with decreased tumor volume in BP3KO mice (r = -0.62, p = 0.03, Spearman's correlation test) in contrast to the increased vessel density associated with increased tumor volume in wild-type mice (r = 0.63, p = 0.02, Spearman's correlation test). These data suggest that endogenous (circulating and/or stromal) IGFBP-3 (i) has a potentially stimulatory role in the expansion of adipose tissue, (ii) can enhance mammary tumor growth in immune-competent mice, potentially by influencing T-cell infiltration into the tumor and (iii) may influence the relationship between tumor vascularity and growth. Citation Format: Tiffany Scully, Carolyn D. Scott, Hasanthi C. de Silva, Sue M. Firth, Stephen M. Twigg, John E. Pintar, Robert C. Baxter. Insulin-like growth factor binding protein-3 (IGFBP-3) enhances obesity-related breast tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 741.