Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer
Open Access
- 26 August 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 33 (28), 3707-3716
- https://doi.org/10.1038/onc.2013.332
Abstract
Tumor metastasis is the leading cause of death among breast cancer patients. PELP1 (proline, glutamic acid and leucine rich protein 1) is a nuclear receptor coregulator that is upregulated during breast cancer progression to metastasis and is an independent prognostic predictor of shorter survival of breast cancer patients. Here, we show that PELP1 modulates expression of metastasis-influencing microRNAs (miRs) to promote cancer metastasis. Whole genome miR array analysis using PELP1-overexpressing and PELP1-underexpressing model cells revealed that miR-200 and miR-141 levels inversely correlated with PELP1 expression. Consistent with this, PELP1 knockdown resulted in lower expression of miR-200a target genes ZEB1 and ZEB2. PELP1 knockdown significantly reduced tumor growth and metastasis compared with parental cells in an orthotopic xenograft tumor model. Furthermore, re-introduction of miR-200a and miR-141 mimetics into PELP1-overexpressing cells reversed PELP1 target gene expression, decreased PELP1-driven migration/invasion in vitro and significantly reduced in vivo metastatic potential in a preclinical model of experimental metastasis. Our results demonstrated that PELP1 binds to miR-200a and miR-141 promoters and regulates their expression by recruiting chromatin modifier histone deacetylase 2 (HDAC2) as revealed by chromatin immunoprecipitation, small interfering RNA and HDAC inhibitor assays. Taken together, our results suggest that PELP1 regulates tumor metastasis by controlling the expression and functions of the tumor metastasis suppressors miR-200a and miR-141.Keywords
This publication has 42 references indexed in Scilit:
- Strategies for the discovery and development of therapies for metastatic breast cancerNature Reviews Drug Discovery, 2012
- Role of Estrogen Receptor Signaling in Breast Cancer MetastasisInternational Journal of Breast Cancer, 2011
- MicroRNA-mediated breast cancer metastasis: from primary site to distant organsOncogene, 2011
- Metastasis-related miRNAs, active players in breast cancer invasion, and metastasisCancer and Metastasis Reviews, 2010
- Metastamir: The Field of Metastasis-Regulatory microRNA Is SpreadingCancer Research, 2009
- MicroRNA involvement in the pathogenesis and management of breast cancerJournal of Clinical Pathology, 2009
- Little Molecules with Big GoalsScience, 2006
- Tumor metastasis: mechanistic insights and clinical challengesNature Medicine, 2006
- MicroRNA Gene Expression Deregulation in Human Breast CancerCancer Research, 2005
- Extracellular matrix 6: Role of matrix metalloproteinases in tumor invasion and metastasisThe FASEB Journal, 1993