TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer
María F Mercogliano1, Mara De Martino1, Leandro Venturutti1
1Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.
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.
Insights
Tumor necrosis factor-alpha (TNFα) induces trastuzumab resistance in HER2-positive breast cancer by upregulating mucin 4 (MUC4). Blocking TNFα or MUC4 can restore trastuzumab sensitivity and improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Trastuzumab is a crucial therapy for HER2-positive breast cancer.
- Resistance to trastuzumab limits its long-term clinical efficacy.
- Tumor necrosis factor-alpha (TNFα) has been implicated in treatment resistance.
Purpose of the Study:
- To elucidate the mechanism of TNFα-induced trastuzumab resistance in HER2-positive breast cancer.
- To investigate therapeutic strategies to overcome this resistance.
- To evaluate the clinical relevance of MUC4 as a predictive biomarker.
Main Methods:
- Overexpression of TNFα in trastuzumab-sensitive breast cancer cells and tumors.
- Assessment of trastuzumab response and antibody-dependent cell cytotoxicity (ADCC).
- Investigation of mucin 4 (MUC4) expression and its role via immunohistochemistry and siRNA.
- Analysis of MUC4 expression in a patient cohort treated with trastuzumab.
Main Results:
- TNFα overexpression conferred trastuzumab resistance, associated with MUC4 upregulation.
- MUC4 reduced trastuzumab binding and impaired ADCC.
- Silencing MUC4 restored trastuzumab sensitivity and antiproliferative effects.
- TNFα-blocking antibodies sensitized resistant cells to trastuzumab.
- MUC4 expression independently predicted poor disease-free survival in patients.
Conclusions:
- TNFα-induced MUC4 expression is a novel mechanism of trastuzumab resistance.
- MUC4 serves as a predictive biomarker for trastuzumab efficacy.
- Combination therapy with TNFα-blocking antibodies and trastuzumab is a potential strategy to overcome resistance.
More Related Videos
11:02Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
06:54Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
