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Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer

Oncogene volume 31, pages 4196–4206 (2012)Cite this article

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Abstract

Estrogen effects on mammary epithelial and breast cancer (BC) cells are mediated by the nuclear receptors ERα and ERβ, transcription factors that display functional antagonism with each other, with ERβ acting as oncosuppressor and interfering with the effects of ERα on cell proliferation, tumor promotion and progression. Indeed, hormone-responsive, ERα+ BC cells often lack ERβ, which when present associates with a less aggressive clinical phenotype of the disease. Recent evidences point to a significant role of microRNAs (miRNAs) in BC, where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. Considering the possibility that ERβ might influence BC cell behavior via miRNAs, we compared miRNome expression in ERβ+ vs ERβ− hormone-responsive BC cells and found a widespread effect of this ER subtype on the expression pattern of these non-coding RNAs. More importantly, the expression pattern of 67 miRNAs, including 10 regulated by ERβ in BC cells, clearly distinguishes ERβ+, node-negative, from ERβ−, metastatic, mammary tumors. Molecular dissection of miRNA biogenesis revealed multiple mechanisms for direct regulation of this process by ERβ+ in BC cell nuclei. In particular, ERβ downregulates miR-30a by binding to two specific sites proximal to the gene and thereby inhibiting pri-miR synthesis. On the other hand, the receptor promotes miR-23b, -27b and 24-1 accumulation in the cell by binding in close proximity of the corresponding gene cluster and preventing in situ the inhibitory effects of ERα on pri-miR maturation by the p68/DDX5-Drosha microprocessor complex. These results indicate that cell autonomous regulation of miRNA expression is part of the mechanism of action of ERβ in BC cells and could contribute to establishment or maintenance of a less aggressive tumor phenotype mediated by this nuclear receptor.

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Acknowledgements

We thank Manuela Ferracin and Massimo Negrini for help with analysis of miRNA expression data from primary tumor samples and useful suggestions, and Luigi Cicatiello, Margherita Mutarelli and Maria Francesca Papa for technical assistance. Work supported by: Italian Association for Cancer Research (grants IG-8586 to AW and IG-8706 to MM), European Union (CRESCENDO IP, contract number LSHM-CT2005-018652), Italian Ministry for Education, University and Research (grant PRIN 2008CJ4SYW_004), University of Salerno (Fondi FARB 2011) and Fondazione con il Sud (grant 2009-PdP-22). CC, FR, GN, MR and RT are fellows of Fondazione con il Sud.

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Authors and Affiliations

  1. Department of General Pathology, Second University of Naples, Napoli, Italy

    O Paris, L Ferraro, O M V Grober, M R De Filippo, G Giurato, E Nola & A Weisz

  2. Laboratory of Molecular Medicine and Genomics, University of Salerno, Baronissi, Italy

    M Ravo, M R De Filippo, G Giurato, G Nassa, R Tarallo, C Cantarella, F Rizzo & A Weisz

  3. Department of Pathology, Regina Elena Cancer Institute, Rome, Italy

    A Di Benedetto & M Mottolese

  4. Genomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany

    V Benes

  5. Department of Biological and Environmental Sciences, University of Sannio, Benevento, Italy

    C Ambrosino

  6. Division of Molecular Pathology and Medical Genomics, ‘SS. Giovanni di Dio e Ruggi d’Aragona’ Hospital, University of Salerno, Salerno, Italy

    A Weisz

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Correspondence to A Weisz.

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Paris, O., Ferraro, L., Grober, O. et al. Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer. Oncogene 31, 4196–4206 (2012). https://doi.org/10.1038/onc.2011.583

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