Associate Professor in Immunology Ohio Univ. Athens, Ohio, United States
Disclosure(s):
Fabian Benencia, PhD: No financial relationships to disclose
Introduction/Rationale: Triple-negative breast cancer (TNBC), a subtype of breast cancer (BrCa) lacking both hormone and HER2 receptors, accounts for 15-20% of all BrCa cases, has a high recurrence rate and is likely to become resistant to traditional chemotherapies. Metformin, a widely used T2D drug, has shown promising anti-cancer effects against some cancers. Its primary mode of action involves the activation of AMP-activated protein kinase, leading to reduced cancer cell proliferation and growth, and alterations in the tumor microenvironment (TME). Interestingly, while evidence suggests a protective effect against ER-positive BrCa, there is less evidence of a benefit for ER-negative or TNBC. We speculate that this could be due to differences in the TME. Macrophages play a critical role in the TME of BrCa, where they can influence disease progression.
Methods: In these studies, we investigated the capability of metformin to block the effect of tumor factors from a mouse TNBC cell line (4T1) on mouse macrophages (RAW 264.7). Macrophages were treated with tumor supernatants in the presence or absence of different concentrations of metformin and then, production of nitrites and expression of costimulatory molecules was evaluated. In addition, direct effect of metformin on macrophage inflammatory activation and migration was evaluated.
Results: We determined that tumor conditioned medium induces the generation of nitric oxide by macrophages and an increase in CD80 expression. Metformin treatment was able to counteract this effect. Further, metformin had a dose dependent effect on macrophage migration and production of nitric oxide in response to LPS.
Conclusion: The response of BC patients to metformin has been contradictory, with no benefit observed for TNBC. We consider that the differences could be associated with the nature of the macrophage population in different BrCa types, with metformin decreasing macrophage responses independently of their M1 or M2-like phenotype.
