Fulvestrant is a selective
estrogen receptor downregulator (SERD) and highly effective antagonist to
hormone-sensitive breast
cancers following failure of previous
tamoxifen or
aromatase inhibitor therapies. However, after prolonged
fulvestrant therapy, acquired resistance eventually occurs in the majority of
breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed
microRNAs (
miRNAs) in acquired
fulvestrant resistance, we compared
antiestrogen-resistant and -sensitive
breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines.
Fulvestrant treatment of
estradiol (E2)- and
fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in
estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or
fulvestrant-induced cell death, thus also conferring
hormone-independent growth and
fulvestrant resistance. In cells with acquired resistance to
fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-
catenin by miR-221/222 contributed to
estrogen-independent growth and
fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two
miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired
fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating
hormone-independent, SERD-resistant
breast cancer.