Tamoxifen downregulation of miR-451 increases 14-3-3ζ and promotes breast cancer cell survival and endocrine resistance

Many estrogen receptor (ER)-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with selective ER modulators (SERMs) such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3 zeta, is upregulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen upregulates 14-3-3 zeta and may promote the development of endocrine resistance is not known. Our findings herein reveal that the tamoxifen upregulation of 14-3-3 zeta results from its ability to rapidly downregulate microRNA (miR)-451 that specifically targets 14-3-3 zeta. The levels of 14-3-3 zeta and miR-451 were inversely correlated, with 14-3-3 zeta being elevated and miR-451 being at a greatly reduced level in tamoxifen-resistant breast cancer cells. Of note, downregulation of miR-451 was selectively elicited by tamoxifen but not by other SERMs, such as raloxifene or ICI182,780 (Fulvestrant). Increasing the level of miR-451 by overexpression, which decreased 14-3-3 zeta, suppressed cell proliferation and colony formation, markedly reduced activation of HER2, EGFR and MAPK signaling, increased apoptosis, and, importantly, restored the growth-inhibitory effectiveness of SERMs in endocrine-resistant cells. Opposite effects were elicited by miR-451 knockdown. Thus, we identify tamoxifen downregulation of miR-451, and consequent elevation of the key survival factor 14-3-3 zeta, as a mechanistic basis of tamoxifen-associated development of endocrine resistance. These findings suggest that therapeutic approaches to increase expression of this tumor suppressor-like miR should be considered to downregulate 14-3-3 zeta and enhance the effectiveness of endocrine therapies. Furthermore, the selective ability of the SERM tamoxifen but not raloxifene to regulate miR-451 and 14-3-3 zeta may assist in understanding differences in their activities, as seen in the STAR (Study of Tamoxifen and Raloxifene) breast cancer prevention trial and in other clinical trials. Oncogene (2012) 31, 39-47; doi: 10.1038/onc.2011.223; published online 13 June 2011