PMID- 20664936
OWN - NLM
STAT- MEDLINE
DCOM- 20101130
LR  - 20190606
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 37
IP  - 3
DP  - 2010 Sep
TI  - Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a 
      basal-like phenotype: new insights into de novo resistance to trastuzumab 
      (Herceptin).
PG  - 669-78
AB  - 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, 
      TGFbeta and VEGF. Semi-quantitative signaling node multi-target sandwich ELISAs 
      revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit 
      of NF-kappaB 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.
FAU - Oliveras-Ferraros, Cristina
AU  - Oliveras-Ferraros C
AD  - Catalan Institute of Oncology (ICO), E-17007 Girona, Catalonia, Spain.
FAU - Vazquez-Martin, Alejandro
AU  - Vazquez-Martin A
FAU - Martin-Castillo, Begona
AU  - Martin-Castillo B
FAU - Perez-Martinez, Maria Carmen
AU  - Perez-Martinez MC
FAU - Cufi, Silvia
AU  - Cufi S
FAU - Del Barco, Sonia
AU  - Del Barco S
FAU - Bernado, Luis
AU  - Bernado L
FAU - Brunet, Joan
AU  - Brunet J
FAU - Lopez-Bonet, Eugeni
AU  - Lopez-Bonet E
FAU - Menendez, Javier A
AU  - Menendez JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Antibodies, Monoclonal/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*pharmacology
MH  - Biomarkers, Tumor/analysis/metabolism
MH  - Breast Neoplasms/*drug therapy/*enzymology/genetics/pathology
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Gene Amplification
MH  - Humans
MH  - Immunophenotyping
MH  - Proteomics
MH  - Receptor, ErbB-2/*antagonists & inhibitors/*biosynthesis/genetics/metabolism
MH  - Receptor, IGF Type 1/metabolism
MH  - Trastuzumab
EDAT- 2010/07/29 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/07/29 06:00
PHST- 2010/07/29 06:00 [entrez]
PHST- 2010/07/29 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - 10.3892/ijo_00000716 [doi]
PST - ppublish
SO  - Int J Oncol. 2010 Sep;37(3):669-78. doi: 10.3892/ijo_00000716.