The Influence of Overweight- and Obesity-associated Mammary Adipose Inflammation on Progression of Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBCs) are a collection of highly proliferative and invasive breast cancers primarily comprised of the basal-like (BBC) and claudin-low (CLBCs) molecular subtypes. We previously reported that weight gain and weight loss regulated pre-neoplastic lesion formation, tumor latency, and tumor progression in C3(1)-TAg mice, a transgenic model of spontaneous BBC. These findings coincided with elevated concentration of hepatocyte growth factor (HGF), ligand for the proto-oncogene cMET, in the mammary microenvironment of high-fat diet (HFD)-fed mice. Thus, herein we conducted a two-phase study investigating whether crizotinib, an inhibitor of cMET, would delay onset of BBC in low-fat (LFD) and HFD-fed C3(1)-TAg mice. When administered prophylactically – before tumor onset – crizotinib did not significantly affect tumor progression or tumor burden. However, with therapeutic treatment following tumor development, crizotinib significantly reduced tumor multiplicity and vascularity in LFD- and HFD-fed C3(1)-TAg mice. These findings emphasize the importance of clarifying “windows of susceptibility” during which HGF/cMET signaling may play disproportionately greater roles in BBC onset and progression. We next hypothesized that adult weight gain and an inflammatory overweight mammary microenvironment would augment CLBC progression, while weight loss before tumor development would normalize overweight-associated tumor promotion. Therefore, a C3(1)-TAg-derived CLBC cell line was orthotopically transplanted into lean, overweight, and formerly overweight female FVB/NJ mice. Indeed, overweight accelerated tumor progression and induced pro-inflammatory changes in the mammary gland, including increased growth factor expression and crown-like structure formation. Weight loss abrogated overweight-induced tumor growth and reduced expression of mitogenic and metastasis-associated signaling pathways in tumors, significantly attenuating inflammation-induced CLBC progression. Interestingly, overweight also resulted in enhanced expression of a mast cell transcriptional signature in whole mammary tissue. Increased mast cell scores were also observed in cancer-adjacent breast tissue of overweight and obese relative to normal weight breast cancer patients. Conversely, lower intratumoral mast cell score was significantly associated with both triple-negative subtype and elevated risk-of-recurrence score in human breast cancers. Taken together, our results support that excess adiposity facilitates TNBC aggression. Further elucidation of adiposity-driven mechanisms of tumor progression and the efficacy of preventive measures such as weight loss could have tremendous potential for public health.Doctor of Philosoph