The Immunosuppressive Microenvironment in BRCA1-IRIS-Overexpressing TNBC Tumors Is Induced by Bidirectional Interaction with Tumor-Associated Macrophages.

ABSTRACT: Tumor-associated macrophages (TAM) promote triple-negative breast cancer (TNBC) progression. Here, we report BRCA1-IRIS-overexpressing (IRISOE) TNBC cells secrete high levels of GM-CSF in a hypoxia-inducible factor-1α (HIF1α)- and a NF-κB-dependent manner to recruit macrophages to IRISOE cells and polarize them to protumor M2 TAMs. GM-CSF triggered TGFβ1 expression by M2 TAMs by activating STAT5, NF-κB, and/or ERK signaling. Despite expressing high levels of TGFβ1 receptors on their surface, IRISOE TNBC cells channeled TGFβ1/TβRI/II signaling toward AKT, not SMAD, which activated stemness/EMT phenotypes. In orthotopic and syngeneic mouse models, silencing or inactivating IRIS in TNBC cells lowered the levels of circulating GM-CSF, suppressed TAM recruitment, and decreased the levels of cir

SUBMITTER: Sami E 

PROVIDER: S-EPMC7056552 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature