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

      , Ph.D., , Ph.D.

      Oncogene

      breast cancer, tamoxifen, endocrine resistance, 14-3-3ζ, miR-451, tumor suppressor

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          Abstract

          Many estrogen receptor-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3ζ, is up-regulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen up-regulates 14-3-3ζ and may promote the development of endocrine resistance is not known. Our findings herein reveal that the tamoxifen up-regulation of 14-3-3ζ results from its ability to rapidly down-regulate miR-451 that specifically targets 14-3-3ζ. The levels of 14-3-3ζ and miR-451 were inversely correlated, with 14-3-3ζ being elevated and miR-451 being at a greatly reduced level in tamoxifen-resistant breast cancer cells. Of note, down-regulation 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 14-3-3ζ, 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 knock-down. Thus, we identify tamoxifen down-regulation of miR-451, and consequent elevation of the key survival factor 14-3-3ζ, 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 microRNA should be considered to down-regulate 14-3-3ζ and enhance the effectiveness of endocrine therapies. Furthermore, the selective ability of the SERM tamoxifen but not raloxifene to regulate miR-451 and 14-3-3ζ may assist in understanding differences in their activities, as seen in the STAR breast cancer prevention trial and in other clinical trials.

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          Most cited references 30

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          Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.

          Tamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis. To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes. The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005. Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years. Incidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events. There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death. Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. clinicaltrials.gov Identifier: NCT00003906.
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            Tamoxifen in the treatment of breast cancer.

             C Osborne (1998)
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              MicroRNAs in vertebrate development.

              The vertebrate genome contains hundreds of small non-coding 'microRNAs' that have been implicated in controlling the expression of potentially thousands of target genes. Presently, only a handful of these targets have been characterized. Recent reports of microRNA 'sensors', microRNA microarrays and the creation of vertebrates that lack all microRNA activity will aid in determining the roles played by microRNAs, and the genes that they regulate, during vertebrate development.
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                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                13 May 2011
                13 June 2011
                5 January 2012
                5 July 2012
                : 31
                : 1
                : 39-47
                Affiliations
                Department of Molecular and Integrative Physiology, University of Illinois and College of Medicine at Urbana-Champaign, Urbana, IL, 61801
                Author notes
                Corresponding Author: Dr. Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, University of Illinois and College of Medicine at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL, 61801, katzenel@ 123456uiuc.edu Phone: 217-333-9769 Fax: 217-244-9906
                Article
                nihpa293396
                10.1038/onc.2011.223
                3175015
                21666713
                Categories
                Article

                Oncology & Radiotherapy

                tumor suppressor, mir-451, tamoxifen, breast cancer, 14-3-3ζ, endocrine resistance

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