Identification of microRNAs associated with tamoxifen resistance in breast cancer

Abstract

Tamoxifen is the most commonly used endocrine therapy for estrogen receptor-positive breast cancer patients. As an estrogen antagonist, tamoxifen competes for binding with estrogen receptor, thereby inhibiting estrogen-dependent gene transcription and tumor growth. However, some breast tumors become estrogen-independent and ultimately develop resistance to the treatment. The mechanisms underlying this transition in the control of cell proliferation remain unclear. Recent work has shown that aberrant expression of microRNAs has been frequently detected in breast cancer and some of which are associated with breast cancer metastasis, poor prognosis, suggesting an important role of microRNAs in breast cancer development and progression. Certain microRNAs negatively regulate AIB1/ACTR, ERα, HER2 and HER3 and deregulation of these genes are well documented to modulate the resistance to tamoxifen in breast cancer. Therefore, we hypothesized that deregulated microRNAs might confer the aberrant expression of their target genes and the development of tamoxifen resistance in breast cancer. To identify microRNAs that might confer resistance to tamoxifen in breast cancer, we examined expression profiles of more than 600 microRNAs in a pair of tamoxifen-sensitive ZR75 and -resistant AK47 breast cancer cell lines using TaqMan Low Density Array (Applied Biosystems). Sixty-five microRNAs were identified substantially downmodulated in the tamoxifen-resistant cell line while 44 microRNAs were found to be upregulated. Consistent with others’ previous findings, our profiling results indicated that miR-221 and miR-222 were overexpressed in the tamoxifen-resistant breast cancer cells. Of the differentially expressed microRNAs, miR-449a and miR-449b were significantly downregulated in the resistant AK47 cells. miR-449a/b expression was also examined in 60 frozen breast tumors by TaqMan Individual MicroRNA Assay (Applied Biosystems). The expression of miR-449a/b was inversely correlated with tumor grade (miR-449a: OR=0.11, 95%CI=0.03-0.38, p<0.001; miR-449b: OR=0.23, 95%CI=0.07-0.70, p=0.008) and strongly associated with estrogen receptor status of the tumor (miR-449a: OR=5.57, 95%CI=1.67-18.55, p=0.003; miR-449b: OR=5.0, 95%CI=1.51-16.56, p=0.006). Our results suggest that miR-449a/b may influence tamoxifen sensitivity in breast cancer cells. Further functional studies are being performed to investigate the regulatory roles of the microRNAs in the development of tamoxifen resistance in breast cancer.