IGH3 in the breast cancer tumor microenvironment increases TGF- signaling to promote cancer progression

Abstract

The secreted extracellular protein, transforming growth factor  induced (TGFBI or IGH3), has context dependent tumor suppressor and tumor promoting roles, similar to TGF-, in part by promoting chemotherapy sensitivity, but then increased IGH3 levels promote cancer progression, with elevated levels correlating to poorer clinical outcomes. IGH3 is regulated by the transforming growth factor-β (TGF-β) signaling pathway, which is an important regulator of breast cancer progression. However, how the breast cancer microenvironment regulates TGF-β signaling during breast cancer progression remains poorly understood. In previous studies, we identified IGH3 as a secreted protein able to promote TGF- signaling. Here, we demonstrate that IGH3 promotes breast tumor growth by promoting activation of the TGF-1 ligand from its latent form in the breast cancer tumor microenvironment. CRISPR/Cas9 silencing of IGH3 decreased tumor growth and decreased activation of latent TGF-1 in a breast cancer models. Mechanistically, IGH3 activates latent TGF-1 through its cysteine rich domain, specifically cysteine 65, and partially through its FAS1-4 domain. Increased IGH3 expression in breast cancer patients correlates with poorer clinical outcomes. These results indicate that TGF-β-mediated induction of IGH3 expression is one mechanism for sustaining elevated TGF-β signaling in the breast cancer tumor microenvironment, with IGH3 setting up positive feed forward loop by promoting activation of latent TGF-1, driving breast cancer growth. Thus, mechanisms to target IGH3 have potential utility in advanced cancers, while assessing IGH3 levels could be a biomarker for chemotherapy resistance and tumor progression.