Adiponectin receptor agonist as potential therapeutic candidate for breast cancer associated with obesity
Résumé
Introduction:Obesity and breast cancer (BC) represent significant health challenges, both of which are closely linked through inflammatory processes. Obesity increases the risk of postmenopausal BC, and adipokines play a pivotal role in this relationship. Adiponectin is a bioactive molecule implicated in regulating BC development, progression, and metastases throughout different metabolic signaling pathways that could be reactivated by targeting adiponectin receptors. Adiponectin receptor agonist (ARA) could specifically replace human adiponectin, activate its receptor, mimic its function and subsequently ameliorate its anti-cancer activity on breast cancer. Methods: The in vitro effect of ARA on BC cells (MCF-7) was investigated by cell viability, cell cycle and apoptosis assays. An innovative co-culture model between obese human Adipospheroids, M1-like proinflammatory Macrophages and BC spheroids (AMC model) was then developed to mimic BC microenvironment and determine how ARA influences BC cells within the context of inflammatory obesity. Results: ARA demonstrated significant effectiveness in inhibiting BC growth in vitro. Treatment with ARA led to a reduction in BC cell viability, an increase in apoptosis, and induced cell cycle arrest. Moreover, within the Adipospheroid-Macrophage-Cancer (AMC) model, ARA exhibited several beneficial effects. Specifically, it decreased the expression of pro-inflammatory cytokines IL6, IL8, and TNFα in M1-like proinflammatory Additionally, ARA reduced the expression of proliferation marker PCNA and angiogenesis regulator VEGF in BC spheroids, further impeding tumor growth and progression. Furthermore, ARA favorably modulated the leptin/adiponectin ratio in Adipospheroids. Conclusion:Our findings indicate that ARA may have dual effects on both obesity and breast cancer through its indirect reactivation of the anti-inflammatory and anti-tumor activity of adiponectin. Ongoing studies are underway to better explore its impact on BC development, with the intention of potentially integrating it into personalized treatment strategies for obese BC patients.
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