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Title 

A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer

Authors 

S NamH R ChangH R JungY GimN Y KimR GrailheH R SeoH S ParkC BalchJinhyuk LeeI ParkS Y JungK C JeongG PowisH LiangE S LeeJ RoY H Kim

Publisher 

Elsevier

Issue Date 

2015

Citation 

Cancer Letters, vol. 356, no. 2, pp. 880-890

Keywords 

Biomarker discoveryBreast cancerDrug resistanceHER2Trastuzumab

Abstract 

Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2+breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance.

ISSN 

0304-3835

Link 

http://dx.doi.org/10.1016/j.canlet.2014.10.038

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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