title: SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B are markers of resistance to neoadjuvant chemotherapy in HER2-negative breast cancer.
abstract: Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicin and cyclophosphamide). We collected, gene expression-profiled, and analyzed 178 HER2-negative breast tumor biopsies ("NKI dataset"). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings in three external datasets, totaling 456 HER2-negative samples. Since these external sets included patients who received differing treatment regimens, the validated markers represent markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p value overlap < 1 × 10(-6)). These five genes identified resistant tumors that could not have been identified by merely taking ER status or proliferation into account. The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival.
authors.affiliation: Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands. j.d.ronde@nki.nl
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: de Ronde
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lips
authors.forename: Lennart
authors.initials: L
authors.lastname: Mulder
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Vincent
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.forename: Marja
authors.initials: M
authors.lastname: Nieuwland
authors.forename: Ron
authors.initials: R
authors.lastname: Kerkhoven
authors.forename: Marie-Jeanne T F D
authors.initials: MJ
authors.lastname: Vrancken Peeters
authors.forename: Gabe S
authors.initials: GS
authors.lastname: Sonke
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000076988:Sulfate Transporters; D043823:Taxoids / Q000008:administration & dosage; D014156:Transcortin / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D000069287:Capecitabine; D027963:Chloride-Bicarbonate Antiporters; D003520:Cyclophosphamide; D003841:Deoxycytidine; D000077143:Docetaxel; D004317:Doxorubicin; D005472:Fluorouracil; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000076988:Sulfate Transporters; D043823:Taxoids; D014156:Transcortin; C544065:AGTR1 protein, human; C469586:BEX1 protein, human; C477083:LAPTM4B protein, human; C534935:SERPINA6 protein, human; C081011:SLC26A3 protein, human; C508053:ERBB2 protein, human