title: A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer.
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.
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Seungyoon
authors.initials: S
authors.lastname: Nam
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Hae Ryung
authors.initials: HR
authors.lastname: Chang
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Hae Rim
authors.initials: HR
authors.lastname: Jung
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Youme
authors.initials: Y
authors.lastname: Gim
authors.affiliation: Core Technology, Institut Pasteur Korea, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Nam Youl
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Core Technology, Institut Pasteur Korea, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Regis
authors.initials: R
authors.lastname: Grailhe
authors.affiliation: Functional Morphometry II, Institut Pasteur Korea, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
authors.forename: Haeng Ran
authors.initials: HR
authors.lastname: Seo
authors.affiliation: Animal Sciences Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Hee Seo
authors.initials: HS
authors.lastname: Park
authors.affiliation: Bioscience Advising, Indianapolis, IN 46227, USA.
authors.forename: Curt
authors.initials: C
authors.lastname: Balch
authors.affiliation: Korean Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
authors.forename: Jinhyuk
authors.initials: J
authors.lastname: Lee
authors.affiliation: Center for Breast Cancer, National Cancer Center of Korea, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Inhae
authors.initials: I
authors.lastname: Park
authors.affiliation: Center for Breast Cancer, National Cancer Center of Korea, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: So Youn
authors.initials: SY
authors.lastname: Jung
authors.affiliation: Biomolecular Function Research Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Kyung-Chae
authors.initials: KC
authors.lastname: Jeong
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Lee
authors.affiliation: Center for Breast Cancer, National Cancer Center of Korea, Goyang-si, Gyeonggi-do 410-769, Republic of Korea.
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea. Electronic address: yhkim@ncc.re.kr.
authors.forename: Yon Hui
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
keywords: Biomarker discovery; Breast cancer; Drug resistance; HER2; Trastuzumab