MUC4 is the principal mediator of TNF-induced trastuzumab resistance and fosters an immunosuppressive tumor microenvironment in HER2+ breast cancer

Abstract

About 13-20 % of breast cancer (BC) patients are HER2 positive (HER2+) and receive trastuzumab (T), an anti-HER2 monoclonal antibody, but 30-50 % of them relapse. We have demonstrated that tumor necrosis factor alpha (TNF) induces the expression of the transmembrane glycoprotein mucin 4 (MUC4) that shields T epitope in HER2, impairing its antitumor effects, and that the soluble and transmembrane TNFα (sTNFα, tmTNFα) inhibitor Etanercept (E) downregulated MUC4 expression and sensitized de novo T-resistant BC xenografts to T. Here, we studied the in vivo participation of MUC4 on T resistance and on antitumor innate immune response. T-resistant JIMT-1 cell line was transduced with a doxycycline (Dox)- inducible MUC4 shRNA construct (JIMT-shMUC4).