Obese conditions induce changes in stromal fibroblast phenotype

Background: Over 40% of American women present a BMI ≥30, which is particularly alarming since obesity confers a worse prognosis for both pre- and postmenopausal breast cancer patients. Although the molecular mechanisms behind this remain unclear, obese conditions have been shown to upregulate certain components of the cancer-associated fibroblast (CAF) secretome and senescence associated secretory phenotype (SASP), both directly correlated with tumorigenesis. However, studies have yet to determine whether obesity induces a cohesive SASP or CAF-like phenotype from any one cell type of the breast tumor microenvironment. Because fibroblasts represent the most common breast tumor cell type, it is of particular importance to investigate obesity-induced changes in this cellular compartment and their effects on cancer cell behavior. Methods: Direct effects of obesity were examined by exposing IMR-90 and HCA2 human fibroblasts to media supplemented with 2% sera from obese women and measuring changes in gene and protein expression, while indirect effects were evaluated by exposing the fibroblasts to conditioned media (CM) from obesity-stimulated MCF-7 and T47D cells and assessing changes in expression of proinflammatory cytokines. Breast cancer cells were also exposed to CM from obesity-stimulated fibroblasts and measured for changes in proliferation, survival, motility, and invasion. Results and Conclusions: Obese conditions induced proinflammatory changes in fibroblasts both directly and indirectly and stimulated changes in the paracrine signaling between fibroblasts and breast cancer cells. These data contribute to the growing evidence implicating obesity in the promotion of breast cancer progression. Additionally, these findings provide a new line of research to develop potential therapeutic targets to improve outcome. Citation Format: Brittany Harlow, Albert Davalos, Andrew Brenner, Christopher Jolly, Stephen Hursting, Linda deGraffenried. Obese conditions induce changes in stromal fibroblast phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5131.