Producción CyT
Tesis
Autoría
Fecha
27/03/2018
Resumen
Información suministrada por el agente en
SIGEVA
Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hampered its clinical benefits. We demonstrated here that TNF? stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines and we explored the mechanism of TNF?-induced trastuzumab resistance and the therapeutic strategies to overcome it. TNF? overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathological findi...
Although trastuzumab administration improved the outcome of HER2-positive breast cancer patients, resistance events hampered its clinical benefits. We demonstrated here that TNF? stimulation in vitro induces trastuzumab resistance in HER2-positive breast cancer cell lines and we explored the mechanism of TNF?-induced trastuzumab resistance and the therapeutic strategies to overcome it. TNF? overexpression turned trastuzumab-sensitive cells and tumors into resistant ones. Histopathological findings revealed mucin foci in TNF?-producing tumors. TNF? induced upregulation of mucin 4 (MUC4) which reduced trastuzumab binding to its epitope and impaired antibody-dependent cell-mediated cytotoxicity (ADCC). Silencing MUC4 enhanced trastuzumab binding, increased ADCC, and overcame trastuzumab and trastuzumabemtansine antiproliferative effects in TNF?-overexpressing cells. Accordingly, administration of TNF?-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 in patients treated with trastuzumab in the adjuvant setting. We also studied the clinical significance of invasive micropapillary carcinoma of the breast (IMPC) in HER2-positive breast cancer patients treated with trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC. We retrospectively studied 86 HER-2-positive breast cancer patients treated with adjuvant trastuzumab. IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression, tumor size and inversely correlated with patient’s age. Disease-free survival was significantly lower in patients with IMPC. MUC4 was strongly expressed in all IMPC cases tested. IMPC appeared as the histological 9 breast cancer subtype with the highest MUC4 expression with respect to IDC, lobular and mucinous carcinoma. We propose MUC4 expression as a useful biomarker to highlight IMPC presence and we concluded that patients with MUC4-positive tumors with IMPC component should require more frequent monitoring and/or more aggressive therapies. Finally, we evaluated differential gene expression of trastuzumab resistant cell lines exerted by stable overexpression of TNF?. We obtained several genes that were regulated not only by TNF? but also by trastuzumab. These genes will constitute novel therapeutic targets to overcome trastuzumab resistance induced by TNF? and/or possible biomarkers to determine the patient’s treatment or response to therapy. In this work we have described a novel trastuzumab resistance mechanism induced by TNF? and MUC4. Taken togheter, these results aim for HER2+ breast cancer remission by overcoming trastuzumab resistance and contributing with a new potential treatment to benefit the patient. In the case of Argentina, it will also allow a better management of the public funds invested in breast cancer treatment.
Ver más
Ver menos
Palabras Clave
TRASTUZUMABRESISTANCERESISTENCIABREAST CANCERHer2Tnf AlfaCANCER DE MAMAT-Dm1
Descargue o solicite el texto completo