The promoter C specific ERalpha isoform is associated with tamoxifen outcome in breast cancer.
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.
Amaral
Sandra
S
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University Tuebingen, Auerbachstrasse 112, 70376, Stuttgart, Germany.
Schroth
Werner
W
Kugler
Sibylle
S
Fritz
Peter
P
Simon
Wolfgang
W
Brauch
Hiltrud
H
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
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D013629:Tamoxifen