title: The promoter C specific ERalpha isoform is associated with tamoxifen outcome in breast cancer.
abstract: Endocrine breast cancer treatment relies on estrogen receptor alpha (ERalpha) assessment, which does not predict response in all cases. We investigated whether ESR1 promoter C driven (ESR1_C) gene expression may shed light on endocrine responsiveness. We investigated archived tumor tissues of 211 patients. Transcript levels of ESR1_C and ESR1_exon3 (all transcripts) were quantified by real-time PCR. mRNA stability was assessed in actinomycin D treated MCF-7 cells. ERalpha protein was quantified using transiently transfected breast cancer cells. Low ESR1_C transcript levels were associated with better overall survival (P = 0.017). High levels of ESR1_C transcript were associated with non-favorable response in tamoxifen treated patients (HR = 2.48; CI 95% 1.24-4.99), an effect that was more pronounced in patients with ERalpha/PgR double-positive tumors (HR = 3.41; CI 95% 1.45-8.04). The ESR1_C isoform had a prolonged mRNA half-life and a more relaxed 5'-UTR structure compared to ESR1_A isoform. ESR1_C levels may aid in the discrimination of patients' endocrine responsiveness.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University Tuebingen, Auerbachstrasse 112, 70376, Stuttgart, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Amaral
authors.forename: Werner
authors.initials: W
authors.lastname: Schroth
authors.forename: Sibylle
authors.initials: S
authors.lastname: Kugler
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Simon
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use*; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D013629:Tamoxifen