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MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways

Oncogene volume 30, pages 1082–1097 (2011)Cite this article

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Abstract

Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two ‘oncomirs’ may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.

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Acknowledgements

We thank Dr Man-Wook Hur for providing the TOPflash and FOPflash plasmids, Jim Powers for assistance with fluorescence microscopy, Dr Meiyun Fan for advice on experiments and Dr Curt Balch for critical comments and paper preparation. The IUB Light Microscopy Imaging Center provided microscopy resources. The microarray studies were carried out using the facilities of the Center for Medical Genomics (Dr H Edenberg, Director and Dr J McClintick) at Indiana University School of Medicine. The Center for Medical Genomics is supported in part by the Indiana Genomics Initiative of Indiana University, which is supported in part by the Lilly Endowment, Inc. This work was supported in part by NIH grants CA085289, CA113001 and CA125806, American Cancer Society Research Scholar Grant 09-244-01, and the Walther Cancer Foundation (Indianapolis).

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Authors and Affiliations

  1. Department of Molecular and Cellular Biochemistry, Interdisciplinary Biochemistry Graduate Program, Indiana University, Bloomington, IN, USA

    X Rao & K P Nephew

  2. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA

    G Di Leva & C M Croce

  3. Department of Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA

    M Li, F Fang, C Hartman-Frey & K P Nephew

  4. Department of Medicine, Department of Immunology and Microbiology, Indiana University School of Medicine, Indianapolis, IN, USA

    C Devlin & M Ivan

  5. Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA

    M E Burow

  6. IU Simon Cancer Center and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA

    C Devlin, M Ivan & K P Nephew

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Rao, X., Di Leva, G., Li, M. et al. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways. Oncogene 30, 1082–1097 (2011). https://doi.org/10.1038/onc.2010.487

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