Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

  • Authors: Cristina Oliveras-Ferraros, Alejandro Vazquez-Martin, Begoña Martin-Castilló, Maria Carmen Pérez-Martínez, Silvia Cufí, Sonia Del Barco, Luis Bernado, Joan Brunet, Eugeni López-Bonet, Javíer A. Menendez
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  • Published online on: Wednesday, September 1, 2010
  • Pages: 669-678
  • DOI: 10.3892/ijo_00000716

Abstract

Pioneering clinical studies in de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab have suggested that HER2 gene-amplification can take place also in a basal-like molecular background to generate basal/HER2+ tumors intrinsically resistant to trastuzumab. Here, we first investigated the unique histogenesis of the basal/HER2+ phenotype in breast carcinomas. The presence of basal CK5/CK6 cytokeratin expression in HER2+ tumors revealed a significant overlap in the histological features of HER2+/CK5/6+ and basal-like breast carcinomas. Basal/HER2+ tumors were typically poorly differentiated, high-grade invasive ductal carcinomas with large geographic necrosis, pushing margins of invasion, syncytial arrangement of tumor cells, ribbon- or festoon-like architecture, squamous metaplasia, stromal lymphocytic infiltrates, high mitotic index and strong p53 positivity. Secondly, we performed low-scale proteomic approaches in JIMT-1 cells, a unique model of HER2-gene amplified trastuzumab-resistant breast carcinoma with a basal-like phenotype, to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors. When applying antibody-based array technology to the extracellular milieu of trastuzumab-refractory JIMT-1 and trastuzumab-sensitive SKBR3 cell cultures, JIMT-1 cells were found to secrete higher amounts of several growth factors including amphiregulin, EGF, IGFBP-6, PDGF-AA, neurotrophins, TGFβ and VEGF. Semi-quantitative signaling node multi-target sandwich ELISAs revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit of NF-κB as compared to trastuzumab-sensitive luminal/HER2+ SKBR3 cells. When simultaneously assessing the activation status of 42 receptor tyrosine kinases (RTK) using a human phospho-RTK array, JIMT-1 cells were found to constitutively display hyperactivation of the insulin-like growth factor-I receptor (IGF-1R). High-content immunofluorescence imaging revealed that activated IGF-1R mainly localized at focal adhesion-like structures in JIMT-1 cells. In vitro wound healing assays suggested that this functional reorganization of the JIMT-1 cytoskeletal reorganization may account for an exacerbated trastuzumab-refractory ‘migratogenic’ phenotype. Forthcoming studies should validate the notion that identification of basal-like immunophenotypes and/or basal-like molecular signatures within HER2+ breast carcinomas may provide rapid means to define subgroups of breast cancer patients likely to display resistance to trastuzumab ab initio.
Journal Cover

September 2010
Volume 37 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

2013 Impact Factor: 2.773
Ranked #30/202 Oncology
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APA
Oliveras-Ferraros, C., Vazquez-Martin, A., Martin-Castilló, B., Pérez-Martínez, M., Cufí, S., Del Barco, S., Bernado, L., Brunet, J., López-Bonet, E., & Menendez, J. (2010). Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin). International Journal of Oncology, 37(3), 669-678.
MLA
Oliveras-Ferraros, Vazquez-Martin, Martin-Castilló, Pérez-Martínez, Cufí, Del Barco, Bernado, Brunet, López-Bonet, and Javíer Menendez. "Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)." International Journal of Oncology International Journal of Oncology 37.3 (2010): 669-678.
Chicago
Oliveras-Ferraros, Vazquez-Martin, Martin-Castilló, Pérez-Martínez, Cufí, Del Barco, Bernado, Brunet, López-Bonet, and Javíer Menendez. "Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)." International Journal of Oncology International Journal of Oncology 37 no. 3 (2010): 669-678.