MiR-449b increased tamoxifen sensitivity through AKT inactivation

Abstract

Tamoxifen is a selective estrogen receptor modifier competing for binding with estrogen receptor, thereby inhibiting estrogen-dependent gene transcription and tumor growth [1]. Nonetheless, about half of the patients that initially respond to the endocrine therapy will ultimately develop acquired resistance. Recent work has shown that aberrant expression of microRNAs has been frequently detected in breast cancer and some of the microRNA target genes are well documented to modulate the sensitivity to tamoxifen in breast cancer [2, 3]. 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 performed global microRNA profiling in a pair of tamoxifen-sensitive ZR75 and -resistant AK47 breast cancer cell lines using TaqMan Low Density Array (Applied Biosystems). Of the differentially expressed microRNAs, miR449b was significantly downregulated in the resistant AK47. We examined miR449b expression in a panel of breast cancer cell lines and the expression of miR449b was generally low in the tamoxifen-resistant cell lines. In addition to AK47, we used an in vitro system LCC2, which was derived from MCF7 by selection against 4-hydroxytamoxifen for further functional experiment. Although ectopic expression of miR449b did not significantly alter cell growth in AK47 and LCC2, it induced early apoptosis in LCC2 cells under tamoxifen treatment. Importantly, overexpression of miR449b increased tamoxifen sensitivity in the breast cancer cell lines. Moreover, miR449b did not alter JNK and MAPK signaling, but decreased the level of Akt phosphorylation. Taken together, these results suggest that miR449b may play a role in the tamoxifen resistance in breast cancer cells through Akt activation. Further functional studies and target identification are being performed to investigate the regulatory roles of the microRNA in the development of tamoxifen resistance in breast cancer.