Abstract
The global increase in overweight and obesity rates represent pressing public health concerns associated with severe comorbidities, amongst a rising incidence and impaired outcome of breast cancer. Yet, biological explanations for how obesity affects breast cancer are incompletely mapped. Herein, the joint impact by differentiated 3T3-L1 adipocytes and obesity-related metabolic conditions on breast cancer cells was evaluated in vitro and adipocyte-derived mediators assessed. Adipokine receptor expression was explored among breast cancer cell lines (n = 47) and primary breast tumors (n = 1,881), where associations with survival outcomes were investigated. Adipocytes and metabolic complications jointly stimulated breast cancer cell proliferation and motility, with phenotype-specific differences. Resistin was among the top modulated adipokines secreted by 3T3-L1 adipocytes under obesity-associated metabolic conditions compared with normal physiology. The newly identified resistin receptor, CAP1, was expressed across a large panel of breast cancer cell lines and primary breast tumors. CAP1 was associated with poor tumor characteristics with higher CAP1 expression among estrogen receptor (ER)-negative tumors, relative to ER-positive tumors (P = 0.025), and higher histological grades (P = 0.016). High CAP1 tumor expression was associated with shorter overall survival (adjusted hazard ratio [HRadj] 1.54; 95% confidence interval [CI], 1.11–2.13) and relapse-free survival (HRadj 1.47; 95% CI, 1.10–1.96), compared with low or intermediate CAP1 expression, particularly among ER-positive tumors or lymph node positive tumors. Together, these translational data demonstrate that the adipocyte secretome promote breast cancer cell proliferation and motility and highlight a potential role of CAP1 regarding breast cancer outcome—results that warrant further investigation to elucidate the obesity-breast cancer link in human pathology.
Highlights
As a consequence of changing diet and lifestyle patterns over the last decades, overweight and obesity are pressing global health concerns with rapidly escalating rates
The present study demonstrates the combined influence by adipocytes and obesity-associated metabolic conditions in promoting breast cancer cell proliferation, along with cellular alterations and induction of more motile phenotypes among both estrogen receptor (ER)-positive and triple-negative breast cancer cells
We further identified resistin among the top modulated adipokines secreted by 3T3-L1 adipocytes under obesity-associated metabolic conditions, constituting a plausible soluble mediator in the link between obesity, metabolic complications and breast cancer
Summary
As a consequence of changing diet and lifestyle patterns over the last decades, overweight and obesity are pressing global health concerns with rapidly escalating rates. Overweight and obese individuals frequently acquire metabolic complications where gradually increasing defects in insulin signaling result in chronic hyperinsulinemia (pre-type 2 diabetes; pre-T2D), insulin resistance (overt-T2D), and impaired insulin secretion (late-T2D) These conditions are associated with hyperglycemia and increased insulin and insulin-like growth factor 1 (IGF1) levels that may contribute to breast cancer initiation, progression and resistance to treatment [4, 5]. Along with these systemic influences of obesity, it is increasingly recognized that a dynamic communication between the different cell types and extracellular matrix within the tumor microenvironment is an integral part of breast cancer development. The cellular and molecular interactions between adipocytes and breast epithelial cells, along with the role of adipocytes and obesity-associated metabolic conditions in tumor progression remain incompletely understood
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