Background: Obesity and advanced age are two major risk factors associated with increased breast cancer (BC) risk and progression. While mechanisms underlying the obesity-BC link are emerging, preclinical and clinical studies typically do not incorporate age as a relevant biological variable that may interact with obesity and other risk factors. Due to systemic features shared between advanced age and obesity, including chronic inflammation and immune dysfunction, we tested the hypothesis that advanced age and obesity similarly enhance BC growth in part through modulation of tumor-intrinsic features. Methods: Young lean, young obese, and aged lean mice received orthotopic transplantation of metM-Wntlung (claudin-low subtype) BC cells into the mammary tissue. Tumor growth was monitored via biweekly palpations, and tumor and lung tissues were excised and stored at study endpoint for subsequent analyses. Lungs were analyzed histologically for metastasis. Differential tumor gene expression was profiled with Affymetrix microarray, analyzed using Gene Set Enrichment Analysis (GSEA), and validated by RT-PCR. Results: Young obese and aged lean mice (relative to young lean mice) displayed accelerated tumor growth and increased tumor mass. Metastasis analysis suggests greater incidence of metastasis in young obese mice compared to young lean and aged lean. Gene expression analyses demonstrate that tumors from aged lean and young obese (relative to young, lean mice) were commonly enriched for genes relating to tumor aggression (e.g. epithelial and mesenchymal transition and angiogenesis) and negatively enriched for markers of antitumor immunity. Conclusions: These findings confirm that obesity and advanced age accelerate BC progression and reveal common biological changes that occur within the tumor microenvironment of aged and obese mice. Further investigation into these age- and obesity-related alterations could provide insight into potential therapeutic targets to improve outcomes for older and/or obese patients.
Nishita T. Sheth (Fri,) studied this question.