Palmitate Promotes Breast Cancer Progression In Vitro Through Induction Of A Senescent-Like Phenotype In Fibroblasts.

Abstract Background: Obesity confers a worse breast cancer prognosis, including an increased risk of recurrence and mortality. While the causative mechanisms have yet to be fully uncovered, emerging evidence implicates palmitate, increased in the obese state, in development of cellular senescence, an inflammatory state associated with breast tumorigenesis in preclinical models. However, studies are warranted to corroborate the impact of palmitate on induction of a cohesive senescent-like phenotype as well as the extent to which palmitate-induced senescence impacts breast tumorigenesis either in vitro or in vivo. This said, we hypothesize that palmitate exposure induces a senescent-like phenotype in fibroblasts, contributing to measures of breast cancer progression. Methods: HCA2, IMR-90, and human mammary fibroblasts were exposed to bovine serum albumin or palmitate in media supplemented with 2% charcoal-stripped fetal bovine serum, after which the cells were measured through qPCR for expression of IL-1a, IL-6 and IL-8, some of the most prominent members of the senescence-associated secretory phenotype. Palmitate-exposed fibroblasts were also stained for senescence-associated beta-galactosidase and BrdU incorporation, well-established senescence markers. Experiments were then repeated with administration of eicosapentaenoic and docosahaexanoic acids to evaluate the potential of omega-3 fatty acids to limit the effects of palmitate on fibroblast senescence. Finally, we assessed the tumor-promoting potential of these palmitate-exposed fibroblasts by culturing MCF-7 and T47D breast cancer cells in their conditioned media and assessing changes in carcinogenic measures. Results and Conclusions: Palmitate induced pro-inflammatory gene expression and SA-beta-gal positivity and decreased proliferation in fibroblasts, while omega-3 fatty acid supplementation reversed these effects. These palmitate-exposed fibroblasts also appeared to be of pathological impact, as exposure to their CM increased proliferation in breast cancer cells. These findings are important in that they support emerging evidence implicating obesity-associated factors in the exacerbation of breast cancer progression as well as indicate the potential of omega-3 fatty acids to improve outcome. Citation Format: Brittany Susanne Harlow, Albert R. Davalos, Andrew J. Brenner, Christopher Jolly, Stefano Tiziani, Stephen D. Hursting, Linda A. deGraffenried. Palmitate promotes breast cancer progression in vitro through induction of a senescent-like phenotype in fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2022.