MicroRNA cluster 221-222 and estrogen receptor α interactions in breast cancer

Gianpiero Di Leva, Pierluigi Gasparini, Claudia Piovan, Apollinaire Ngankeu, Michela Garofalo, Cristian Taccioli, Marilena V. Iorio, Meng Li, Stefano Volinia, Hansjuerg Alder, Tatsuya Nakamura, Gerard Nuovo, Yunlong Liu, Kenneth P. Nephew, Carlo M. Croce

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244 Scopus citations


Background: Several lines of evidence have suggested that estrogen receptor α (ERα)-negative breast tumors, which are highly aggressive and nonresponsive to hormonal therapy, arise from ERα-positive precursors through different molecular pathways. Because microRNAs (miRNAs) modulate gene expression, we hypothesized that they may have a role in ER-negative tumor formation. Methods: Gene expression profiles were used to highlight the global changes induced by miRNA modulation of ERα protein. miRNA transfection and luciferase assays enabled us to identify new targets of miRNA 206 (miR-206) and miRNA cluster 221-222 (miR-221-222). Northern blot, luciferase assays, estradiol treatment, and chromatin immunoprecipitation were performed to identify the miR-221-222 transcription unit and the mechanism implicated in its regulation. Results: Different global changes in gene expression were induced by overexpression of miR-221-222 and miR-206 in ER-positive cells. miR-221 and-222 increased proliferation of ERα-positive cells, whereas miR-206 had an inhibitory effect (mean absorbance units [AU]: miR-206: 500 AU, 95% confidence interval [CI]) = 480 to 520; miR-221: 850 AU, 95% CI = 810 to 873; miR-222: 879 AU, 95% CI = 850 to 893; P <. 05). We identified hepatocyte growth factor receptor and forkhead box O3 as new targets of miR-206 and miR-221-222, respectively. We demonstrated that ERα negatively modulates miR-221 and-222 through the recruitment of transcriptional corepressor partners: nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone receptor. Conclusions: These findings suggest that the negative regulatory loop involving miR-221-222 and ERα may confer proliferative advantage and migratory activity to breast cancer cells and promote the transition from ER-positive to ER-negative tumors.

Original languageEnglish (US)
Pages (from-to)706-721
Number of pages16
JournalJournal of the National Cancer Institute
Issue number10
StatePublished - May 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Di Leva, G., Gasparini, P., Piovan, C., Ngankeu, A., Garofalo, M., Taccioli, C., Iorio, M. V., Li, M., Volinia, S., Alder, H., Nakamura, T., Nuovo, G., Liu, Y., Nephew, K. P., & Croce, C. M. (2010). MicroRNA cluster 221-222 and estrogen receptor α interactions in breast cancer. Journal of the National Cancer Institute, 102(10), 706-721. https://doi.org/10.1093/jnci/djq102