Adipocytes and Obesity-Related Conditions Jointly Promote Breast Cancer Cell Growth and Motility: Associations With CAP1 for Prognosis

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.

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…Mammary adipose tissue in the tumor microenvironment displays persistent inflammation and harbors crown like structures, which are well-known inflammatory foci (62). We therefore propose that mammary adipose tissue displays local inflammation (as a result of DIO) similar to what is observed in visceral adipose tissue of obese individuals (52,63) and as a result may play a significant role in obesity-induced breast cancer treatment resistance. It is speculated that treatment resistance may be the result of inflammation found in the mammary adipose tissue as a result of the HFD and doxorubicin treatment.…”

“…Leptin and resistin are well-known adipokines linked to breast cancer (51). Both are secreted primarily by adipose tissue, increase with higher degrees of adiposity, and has been implicated for their role in obesity, inflammation, and breast tumorigenesis (51)(52)(53). Breast cancer patients are characterized by high serum leptin concentrations as well as increased leptin receptor expression especially in higher pathological grade tumor tissues and patients who develop resistance to anti-cancer treatments (54,55).…”

CAPt’n of Actin Dynamics: Recent Advances in the Molecular, Developmental and Physiological Functions of Cyclase-Associated Protein (CAP)

“…Obesity represents a major risk for developing several types of cancer, including breast cancer (Calle and Kaaks, 2004). Resistin is among the top modulated adipokines secreted by adipocytes under obesity-associated metabolic conditions and therefore represents a plausible soluble mediator in the link between obesity, metabolic complications and breast cancer via the binding to CAP1 (Rosendahl et al, 2018). In a study, CAP1 gene and Resistin gene variants were associated with increased risk of breast cancer among Mexican women (Munoz-Palomeque et al, 2018).…”

“…In a study, CAP1 gene and Resistin gene variants were associated with increased risk of breast cancer among Mexican women (Munoz-Palomeque et al, 2018). CAP1 is expressed across a large panel of breast cancer cell lines and primary human tumor and high CAP1 expression is associated with poor tumor characteristics and impaired prognosis among breast cancer patients (Rosendahl et al, 2018). Low CAP1 tumor expression was associated with higher body fatness and worse survival outcomes in breast cancer patients (Bergqvist et al, 2020).…”

Adipocytes in Breast Cancer, the Thick and the Thin

“…The resistin receptor adenylyl cyclase-associated protein 1 (CAP1) was shown to be expressed by numerous BC cell lines and primary human tumors. Moreover, its high expression in BC patients was associated with characteristics of aggressiveness and poor prognosis [130].…”