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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

TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer

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  • Medientyp: E-Artikel
  • Titel: TNFα-Induced Mucin 4 Expression Elicits Trastuzumab Resistance in HER2-Positive Breast Cancer
  • Beteiligte: 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
  • Erschienen: American Association for Cancer Research (AACR), 2017
  • Erschienen in: Clinical Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-16-0970
  • ISSN: 1078-0432; 1557-3265
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>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).</jats:p><jats:p>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.</jats:p>
  • Zugangsstatus: Freier Zugang