The Role of Obesity-Associated Adipose Tissue Inflammation in Breast Cancer Growth, Progression, and Metastasis
Creators: name: Eisenbeis, Lydia
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2020

description: Breast cancer is currently the second leading cause of cancer-related death in the United States and the most commonly diagnosed cancer among women. Approximately 85,000 new cancer cases per year can be attributed to obesity, a known risk factor for breast cancer that alters key physiological pathways linked to tumorigenesis and metastasis. In the obese state, adipose tissue undergoes remodeling which promotes chronic, low-grade inflammation. This inflammatory response can result in increased serum levels of several proteins involved in cellular growth, proliferation and survival that are also known to support breast cancer progression and metastasis. In addition, obesity-associated adipocytes are known to secrete pro-inflammatory cytokines which have been indicated as potential mediators in the progression of breast cancer. Targeting inflammation using non-steroidal anti-inflammatory drugs (NSAIDs), such as Sulindac, has shown promising results in decreasing breast cancer recurrence; however, additional research is necessary to assess their efficacy in obesity-associated breast cancer models. This study therefore aims to investigate the role of obesity-associated changes in the adipose secretome in driving breast cancer progression and metastasis.
To model the response of breast cancer cells to alterations in the adipose secretome in vitro, we cultured multiple metastatic breast cancer cell lines in fat conditioned media (FCM) derived from the mammary fat pads of female C57Bl/6 mice on Control, diet-induced obesity (DIO), and DIO+Sulindac diets. Phenotypic assays including MTT and wound-healing assays were conducted to determine proliferative and migratory differences between the varying FCM diet conditions. Following characterization, pro-inflammatory mediators were identified using a Luminex assay and gene expression analysis in mammary adipose tissue. The efficacy of Sulindac as a strategy for mitigating obesity-associated adipose tissue inflammation and breast cancer progression was evaluated. 
Treatment with FCM, regardless of the diet group from which the FCM was obtained, increased both cell viability and migration of multiple breast cancer cell lines in vitro, indicating its role in promoting cancer cell proliferation and metastasis. No significant differences were observed between the Control, DIO and DIO+Sulindac diet conditions following phenotypic analysis; however, gene expression and multiplexed cytokine analyses revealed increased concentrations of pro-inflammatory cytokines in the DIO conditions relative to both control and DIO+Sulindac conditions. Our FCM studies suggest that obesity-associated cytokine changes in the adipose tissue secretome, and concomitant transcriptional changes in the adipose tissue itself, increase the proliferative and metastatic potential of various breast cancer cell lines. Supplementation with Sulindac may offset the procancer effects of obesity by reducing proinflammatory cytokines in the secretome and normalizing inflammatory gene expression.