HER2 and p95HER2 differentially regulate miRNA expression in MCF-7 breast cancer cells and downregulate MYB proteins through miR-221/222 and miR-503
Gorbatenko, A. (Section for Cell Biology and Physiology. Department of Biology. Faculty of Science. University of Copenhagen)
Søkilde, R. (Department of Clinical Sciences Lund. Oncology and Pathology. Faculty of Medicine. Lund University)
Sorensen, E. E. (Section for Cell Biology and Physiology. Department of Biology. Faculty of Science. University of Copenhagen)
Newie, I. (Department of Clinical Sciences Lund. Oncology and Pathology. Faculty of Medicine. Lund University)
Persson, H. (Department of Clinical Sciences Lund. Oncology and Pathology. Faculty of Medicine. Lund University)
Morancho, Beatriz (Vall d'Hebron Institut d'Oncologia)
Arribas, Joaquín V (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Litman, T. (Department of International Health. Immunology and Microbiology. University of Copenhagen)
Rovira, Carlos (Department of Clinical Sciences Lund. Oncology and Pathology. Faculty of Medicine. Lund University)
Pedersen, S. F. (Section for Cell Biology and Physiology. Department of Biology. Faculty of Science. University of Copenhagen)

Date:	2019
Abstract:	The HER2 oncogene and its truncated form p95HER2 play central roles in breast cancer. Here, we show that although HER2 and p95HER2 generally elicit qualitatively similar changes in miRNA profile in MCF-7 breast cancer cells, a subset of changes are distinct and p95HER2 shifts the miRNA profile towards the basal breast cancer subtype. High-throughput miRNA profiling was carried out 15, 36 and 60 h after HER2 or p95HER2 expression and central hits validated by RT-qPCR. miRNAs strongly regulated by p95HER2 yet not by HER2, included miR-221, miR-222, miR-503, miR-29a, miR-149, miR-196 and miR-361. Estrogen receptor-α (ESR1) expression was essentially ablated by p95HER2 expression, in a manner recapitulated by miR-221/-222 mimics. c-Myb family transcription factors MYB and MYBL1, but not MYBL2, were downregulated by p95HER2 and by miR-503 or miR-221/-222 mimics. MYBL1 3'UTR inhibition by miR-221/222 was lost by deletion of a single putative miR-221/222 binding sites. p95HER2 expression, or knockdown of either MYB protein, elicited upregulation of tissue inhibitor of matrix metalloprotease-2 (TIMP2). miR-221/222 and -503 mimics increased, and TIMP2 knockdown decreased, cell migration and invasion. A similar pathway was operational in T47D- and SKBr-3 cells. This work reveals important differences between HER2- and p95HER2- mediated miRNA changes in breast cancer cells, provides novel mechanistic insight into regulation of MYB family transcription factors by p95HER2, and points to a role for a miR-221/222- MYB family-TIMP2 axis in regulation of motility in breast cancer cells.
Grants:	Instituto de Salud Carlos III PI16-00253
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Scientific reports, Vol. 9 Núm. 1 (january 2019) , p. 3352, ISSN 2045-2322

DOI: 10.1038/s41598-019-39733-x
PMID: 30833639

16 p, 5.4 MB

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