MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways

Abstract

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 over-expression 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.

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

“…In breast cancer, the role of miRNAs in tamoxifen resistance, through regulation of cell cycle regulatory proteins, has been suggested. In particular, ectopic expression of miR-101, miR-206 and miR-221/miR-222 was found to render ER-positive MCF-7 cells resistant to tamoxifen (150)(151)(152)(153). These miRNAs were also found to be significantly increased in Her2-positive primary human breast cancer tissues indicating an interrelationship between miR-221/222 expression and Her2 overexpression in primary breast tumors that are generally resistant to tamoxifen therapy.…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…Recently, it has been indicated that these miRNAs induce resistance to the selective ER downregulator, and this was caused by the activation of β-catenin and the repression of transforming growth factor-β-mediated growth inhibition. 54 Lu et al 55 demonstrated that miR-221, miR-222 and miR-181b directly target tissue inhibitor of metalloproteinases (TIMP)3, and MCF7 cells that had been subjected to TIMP3 knockdown were found to be able to Figure 2 Biogenesis and function of microRNA (miRNA). miRNA genes are transcribed by RNA polymerase II (Pol II) in the nucleus to generate primary miRNA (pri-miRNA).…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…miRNAs are also associated with chemosensitivity and radiation sensitivity. miR-221/222 are overexpressed in fulvestrant-resistant breast cancer cells and are associated with the acquisition of fulvestrant resistance [113] . Furthermore, up-regulation of miR-221/222 in breast cancer cells also causes tamoxifen resistance by targeting p27 [114] .…”