Abstract P1-08-02: Omega-3 fatty acids modulate the ability of obese conditions to induce of a proinflammatory phenotype in fibroblasts

Abstract

Background: Approximately 40% of American women suffer from obesity, and about 1 in 8 women will be diagnosed with breast cancer during her lifetime. The concurrence of these trends has the potential to be particularly detrimental, as obesity confers a worse prognosis for both pre- and postmenopausal breast cancer patients. While the precise mechanisms by which obesity impacts breast cancer prognosis remain to be discovered, evidence suggests that obesity upregulates components of cancer-associated fibroblast (CAF) and senescent cell secretomes, both causally associated with carcinogenesis. Specifically, obesity has been shown to induce expression of the secretory products prostaglandin E2, high mobility group protein B1, interleukin (IL)-6, IL-1 beta, and matrix metalloproteinase-1, the expression of which can be modulated by omega-3 fatty acid-induced signaling. However, studies have yet to determine whether obesity imparts these proinflammatory phenotypes in any individual cell type in the breast tumor microenvironment as well as whether these phenotypes can be modulated by administration of omega-3 fatty acids. This said, we hypothesize that fatty acids modulate the ability of obese conditions to induce a proinflammatory senescent- or CAF-like fibroblast phenotype and thus impact breast cancer progression. Because fibroblasts constitute 80% of the tumor stromal mass, it is of the utmost importance to study obesity-stimulated changes in this cellular compartment and their effects on tumor progression. Methods: Fibroblasts were exposed to sera derived from lean or obese women with and without omega-3 fatty acid supplementation and assessed for changes in expression of proinflammatory genes, including IL-1α, IL-6, and IL-8, as well as nuclear localization of p65, a subunit of the NF-kB transcription factor, which transcribes about 75% of genes related to the senescent secretome. Conditioned media (CM) from these fibroblasts were then applied to breast cancer cells to assess measures of cancer cell aggressiveness. Finally, as an ex vivo study, breast tissue samples from lean and obese women and mice were compared for concentration of proinflammatory, senescent fibroblasts by immunohistochemical analyses. Results: Gene and protein expression analyses demonstrated that obese conditions induced a proinflammatory phenotype in fibroblasts, an effect at least partially modulated by omega-3 fatty acids. These phenotypic changes were not without pathological consequence: CM from obesity-stimulated fibroblasts impacted in vitro measures of breast cancer cell aggressiveness to a greater degree than lean sera-stimulated fibroblasts. Conclusions: While correlative, these data contribute to the identification of a link between obesity and proinflammatory, senescent phenotypes and will ultimately allow for elucidation of the means by which obese conditions confer a worse prognosis for breast cancer patients. In addition, these findings will contribute to our understanding of crosstalk within the tumor microenvironment and inform our pursuit for the development of novel therapeutic targets. Citation Format: Brittany Harlow, Albert Davalos, Andrew Brenner, Christopher Jolly, Stefano Tiziani, Stephen Hursting, Linda deGraffenried. Omega-3 fatty acids modulate the ability of obese conditions to induce of a proinflammatory phenotype in fibroblasts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-08-02.