Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer.
BACKGROUND
Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.


METHODS
BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model.


RESULTS
Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.


CONCLUSIONS
BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy.
Godinho
M F E
MF
Department of Pathology, Josephine Nefkens Institute, Erasmus MC-University Medical Center Rotterdam, Rotterdam, 3000 CA, The Netherlands.
Sieuwerts
A M
AM
Look
M P
MP
Meijer
D
D
Foekens
J A
JA
Dorssers
L C J
LC
van Agthoven
T
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012189:Retrospective Studies; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use*
D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; C553206:BCAR4 non-coding RNA, human; D054316:Biomarkers, Pharmacological; D050719:Crk-Associated Substrate Protein; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D013629:Tamoxifen