Obese adipose derived secretome stimulates triple negative breast cancer via stimulation of the mTOR pathway

Abstract Background: Breast cancer remains the most common cancer amoung women with multipe risk factors including smoking, genetics, environmental factors, and obesity. Smoking and obesity are the top two risk factors for development of breast cancer, with smoking increasing the risk of development by 21% and obesity by 20-40%. Obesity increases the risk for all breast cancer subtypes, including triple negative breast cancer (TNBC) that is null for estrogen and progesterone receptors and the tyrosine kinase receptor, HER2. To this end, recent retrospective patient studies have shown that the majority of patients with TNBC were obese at the time of diagnosis. In addition, obese patients had a higher TNBC tumor grade and a higher staging. However, the signaling mechanisms that promote the progression of TNBC in obesity are not well understood. We published that adipose tissue (AT) derived secretome (ADS) in obesity promotes the invasiveness of estrogen receptor positive breast cancer cells. Based on these prior findings, we hypothesize ADS in obesity acts on TNBC cells to induce mTOR activity and in turn stimulates TNBC cell migration and invasiveness. Methods: De-identified peritumor (PT) breast AT samples were obtained with patient consent at the time of surgery for breast cancer treatment. Breast AT samples were cultured in serum free culture medium for 24 hours. After the incubation, the AT conditioned media was clarified by centrifugation. For this study, considered BMI less than 30 as lean-ADS (LADS) and BMI of 30 or greater as obese-ADS (OADS). ADS diluted 1:10 in serum free culture medium was applied to human MDA-MB-231 and MDA-MB-436 TNBC cells. Cell migration was assayed by the scratch assay. Images were taken at time 0, and 24 hours. Analysis was performed using image J. Western blot studies were performed to assay the levels of total and/or phosphorylated proteins. Results: OADS stimulated a statistically significant increase (1.5 fold) in TNBC cell migration compared with LADS. The increase in TNBC cell migration was associated with a significant increase (1.5 fold) in phosphorylated S6 in TNBC cells treated with OADS relative to LADS. Conclusion: Increases in mTOR activity in TNBC cells in response to OADS is associated with increased TNBC cell migration. Citation Format: Cora E. Miracle, Travis Salisbury, Chelsea McCallister. Obese adipose derived secretome stimulates triple negative breast cancer via stimulation of the mTOR pathway [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C096.