Abstract
Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3'-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3'-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.
Highlights
Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER؉) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression
ERBB2 is post-transcriptionally up-regulated in tamoxifenresistant (TAMR) ER؉ breast cancer cells
ERϩ breast cancer cells (MCF7 and T47D) with acquired tamoxifen resistance were generated by chronic treatment with tamoxifen (Fig. 1A) [41, 42]
Summary
Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER؉) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. In TAMR ER؉ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. Increasing evidence has supported the critical roles of HuR in breast cancer initiation, progression, metastasis, and drug resistance through its modulation of the stability of relevant transcripts [29]. Forced expression of miR-26a/b and/or depletion of HuR, which decreased ERBB2 expression, enhanced the response of the TAMR breast cancer cells to tamoxifen. We further elucidated a novel mechanism leading to up-regulated HuR expression in TAMR breast cancer cells, in which higher levels of CSTF2 mediate increased production of an HuR mRNA isoform with a shorter 3Ј-UTR through APA, resulting in higher HuR protein expression
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