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

O. Paris, L. Ferraro, O. M V Grober, M. Ravo, M. R. De Filippo, G. Giurato, G. Nassa, R. Tarallo, C. Cantarella, F. Rizzo, A. Di Benedetto, M. Mottolese, V. Benes, C. Ambrosino, E. Nola, A. Weisz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4196-4206
Number of pages11
JournalOncogene
Volume31
Issue number38
DOIs
Publication statusPublished - Sep 20 2012

Keywords

  • breast cancer
  • estrogen receptor beta
  • gene transcription
  • hormones
  • microRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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