Resistance to the
antiestrogen tamoxifen remains a major problem in the management of
estrogen receptor-positive
breast cancer. Knowledge on the resistance mechanisms is needed to develop more effective
therapies.
Breast cancer antiestrogen resistance 4 (BCAR4) was identified in a functional screen for genes involved in
tamoxifen resistance. BCAR4 is expressed in 27% of primary
breast tumors. In patients treated with
tamoxifen for metastized disease high BCAR4
mRNA levels are associated with reduced clinical benefit and progression-free survival. Regarding
tumor aggressiveness high BCAR4
mRNA levels are associated with a shorter
metastasis free survival and overall survival. In the present study, we investigated the role of BCAR4 in endocrine resistance. Forced expression of BCAR4 in human ZR-75-1 and MCF7
breast cancer cells resulted in cell proliferation in the absence of
estrogen and in the presence of various
antiestrogens. Inhibition of
estrogen receptor 1 (ESR1) expression with
small interfering RNA (
siRNA), implied that the BCAR4-induced mechanism of resistance is independent of ESR1. Highly conserved BCAR4 homologues of rhesus monkey, green monkey, and the less conserved common marmoset gene induced
tamoxifen-resistant cell proliferation, in contrast to the distant BCAR4 homologues of bovine and rabbit. Injection of BCAR4-expressing ZR-75-1 cells into nude mice resulted in rapidly growing
tumors. In silico analysis showed that BCAR4
mRNA is highly expressed in human placenta and oocyte, and absent in other normal tissues. In conclusion, BCAR4 is a strong transforming gene causing
estrogen-independent growth and
antiestrogen resistance, and induces
tumor formation in vivo. Due to its restricted expression, BCAR4 may be a good target for treating
antiestrogen-resistant
breast cancer.