PURPOSE: The decision for treating breast cancer patients with trastuzumab is based on HER-2 amplification and/or overexpression. METHODS: Using MCF-7 cells (Her-2 +/-) engineered to overexpress heregulin (MCF-7/HRG), a ligand for the Her-2/3/4 network, we investigated whether HRG-induced transactivation of Her-2 affected breast cancer cell sensitivity to chemotherapy and whether trastuzumab trigger receptor-enhanced chemosensitivity (REC) when combined with chemotherapy without Her-2 overexpression. RESULTS: MCF-7/HRG cells were more than 10-fold resistant to the alkylating agent cisplatin (CDDP), while trastuzumab coexposure completely reversed HRG-promoted CDDP resistance. A synergistic interaction between trastuzumab in combination with CDDP (paclitaxel or vincristine) was obtained in MCF-7/HRG cells. Trastuzumab prevented activation of the antiapoptotic and proliferative cascades and inhibited HRG-induced Her-2/3 phosphorylation. CDDP efficacy was enhanced by trastuzumab in cells expressing endogenously high levels of HRG. Conversely, trastuzumab coexposure was ineffective in enhancing chemotherapy efficacy in cells that did not secrete HRG, such as MCF-7 cells overexpressing a structural mutated HRG isoform. Therefore, trastuzumab-induced REC, in the absence of Her-2 overexpression, occurs through the kinase activity of Her-2/3. Interestingly, HRG expression in tumor biopsies from invasive breast carcinomas (n = 189) revealed that, whereas the minority (12%) of Her-2 positive tumors (n = 60; 32%) demonstrated Her-2 phosphorylation, the majority (67%) of HRG-overexpressing and Her-2 tumors (n = 57; 30%) were in active Her-2 status. CONCLUSION: We demonstrate that assessment of HRG expression and Her-2 activation define a particular breast cancer patient population for which trastuzumab plus CDDP or taxol are extremely efficient without Her-2 overexpression.
PURPOSE: The decision for treating breast cancerpatients with trastuzumab is based on HER-2 amplification and/or overexpression. METHODS: Using MCF-7 cells (Her-2 +/-) engineered to overexpress heregulin (MCF-7/HRG), a ligand for the Her-2/3/4 network, we investigated whether HRG-induced transactivation of Her-2 affected breast cancer cell sensitivity to chemotherapy and whether trastuzumab trigger receptor-enhanced chemosensitivity (REC) when combined with chemotherapy without Her-2 overexpression. RESULTS: MCF-7/HRG cells were more than 10-fold resistant to the alkylating agent cisplatin (CDDP), while trastuzumab coexposure completely reversed HRG-promoted CDDP resistance. A synergistic interaction between trastuzumab in combination with CDDP (paclitaxel or vincristine) was obtained in MCF-7/HRG cells. Trastuzumab prevented activation of the antiapoptotic and proliferative cascades and inhibited HRG-induced Her-2/3 phosphorylation. CDDP efficacy was enhanced by trastuzumab in cells expressing endogenously high levels of HRG. Conversely, trastuzumab coexposure was ineffective in enhancing chemotherapy efficacy in cells that did not secrete HRG, such as MCF-7 cells overexpressing a structural mutated HRG isoform. Therefore, trastuzumab-induced REC, in the absence of Her-2 overexpression, occurs through the kinase activity of Her-2/3. Interestingly, HRG expression in tumor biopsies from invasive breast carcinomas (n = 189) revealed that, whereas the minority (12%) of Her-2 positive tumors (n = 60; 32%) demonstrated Her-2 phosphorylation, the majority (67%) of HRG-overexpressing and Her-2tumors (n = 57; 30%) were in active Her-2 status. CONCLUSION: We demonstrate that assessment of HRG expression and Her-2 activation define a particular breast cancerpatient population for which trastuzumab plus CDDP or taxol are extremely efficient without Her-2 overexpression.
Authors: Cleo Yi-Fang Lee; Yuan Lin; Scott V Bratman; Weiguo Feng; Angera H Kuo; Ferenc A Scheeren; Jesse M Engreitz; Sushama Varma; Robert B West; Maximilian Diehn Journal: Cancer Res Date: 2013-10-31 Impact factor: 12.701
Authors: Edith A Perez; Robert B Jenkins; Amylou C Dueck; Anne E Wiktor; Patrick P Bedroske; S Keith Anderson; Rhett P Ketterling; William R Sukov; Kazunori Kanehira; Beiyun Chen; Xochiquetzal J Geiger; Cathy A Andorfer; Ann E McCullough; Nancy E Davidson; Silvana Martino; George W Sledge; Peter A Kaufman; Leila A Kutteh; Julie R Gralow; Lyndsay N Harris; James N Ingle; Wilma L Lingle; Monica M Reinholz Journal: J Clin Oncol Date: 2011-01-18 Impact factor: 44.544
Authors: Edith A Perez; Monica M Reinholz; David W Hillman; Kathleen S Tenner; Matthew J Schroeder; Nancy E Davidson; Silvana Martino; George W Sledge; Lyndsay N Harris; Julie R Gralow; Amylou C Dueck; Rhett P Ketterling; James N Ingle; Wilma L Lingle; Peter A Kaufman; Daniel W Visscher; Robert B Jenkins Journal: J Clin Oncol Date: 2010-08-09 Impact factor: 44.544
Authors: Elizabeth A Hopper-Borge; Rochelle E Nasto; Vladimir Ratushny; Louis M Weiner; Erica A Golemis; Igor Astsaturov Journal: Expert Opin Ther Targets Date: 2009-03 Impact factor: 6.902
Authors: Amylou C Dueck; Monica M Reinholz; Xochiquetzal J Geiger; Kathleen Tenner; Karla Ballman; Robert B Jenkins; Darren Riehle; Beiyun Chen; Ann E McCullough; Nancy E Davidson; Silvana Martino; George W Sledge; Peter A Kaufman; Leila A Kutteh; Julie Gralow; Lyndsay N Harris; James N Ingle; Wilma L Lingle; Edith A Perez Journal: Clin Cancer Res Date: 2013-08-21 Impact factor: 12.531
Authors: Sherene Loi; Christos Sotiriou; Benjamin Haibe-Kains; Francoise Lallemand; Nelly M Conus; Martine J Piccart; Terence P Speed; Grant A McArthur Journal: BMC Med Genomics Date: 2009-06-24 Impact factor: 3.063