TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer. Academic Article uri icon

Overview

abstract

  • PURPOSE: Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hamper its clinical benefits. We demonstrated that TNFα stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines. Here, we explored the mechanism of TNFα-induced trastuzumab resistance and the therapeutic strategies to overcome it. EXPERIMENTAL DESIGN: Trastuzumab-sensitive breast cancer cells, genetically engineered to stably overexpress TNFα, and de novo trastuzumab-resistant tumors, were used to evaluate trastuzumab response and TNFα-blocking antibodies effectiveness respectively. Immunohistochemistry and antibody-dependent cell cytotoxicity (ADCC), together with siRNA strategy, were used to explore TNFα influence on the expression and function of its downstream target, mucin 4 (MUC4). The clinical relevance of MUC4 expression was studied in a cohort of 78 HER2-positive breast cancer patients treated with adjuvant trastuzumab. RESULTS: TNFα overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathologic findings revealed mucin foci in TNFα-producing tumors. TNFα induced upregulation of MUC4 that reduced trastuzumab binding to its epitope and impaired ADCC. Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumab-emtansine antiproliferative effects in TNFα-overexpressing cells. Accordingly, administration of TNFα-blocking antibodies downregulated MUC4 and sensitized de novo trastuzumab-resistant breast cancer cells and tumors to trastuzumab. In HER2-positive breast cancer samples, MUC4 expression was found to be an independent predictor of poor disease-free survival (P = 0.008). CONCLUSIONS: We identified TNFα-induced MUC4 expression as a novel trastuzumab resistance mechanism. We propose MUC4 expression as a predictive biomarker of trastuzumab efficacy and a guide to combination therapy of TNFα-blocking antibodies with trastuzumab. Clin Cancer Res; 23(3); 636-48. ©2016 AACR.

authors

  • Mercogliano, María F
  • De Martino, Mara
  • Venturutti, Leandro
  • Rivas, Martín A
  • Proietti, Cecilia J
  • Inurrigarro, Gloria
  • Frahm, Isabel
  • Allemand, Daniel H
  • Deza, Ernesto Gil
  • Ares, Sandra
  • Gercovich, Felipe G
  • Guzmán, Pablo
  • Roa, Juan C
  • Elizalde, Patricia V
  • Schillaci, Roxana

publication date

  • October 3, 2016

Research

keywords

  • Antineoplastic Agents, Immunological
  • Breast Neoplasms
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Mucin-4
  • Neoplasm Proteins
  • Receptor, ErbB-2
  • Trastuzumab
  • Tumor Necrosis Factor-alpha

Identity

Scopus Document Identifier

  • 85012301055

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-16-0970

PubMed ID

  • 27698002

Additional Document Info

volume

  • 23

issue

  • 3