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Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer

Oncogene volume 33, pages 3707–3716 (2014)Cite this article

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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.

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Acknowledgements

This study was supported by the NIH/NCI Grant CA095681 (R.K.V.) T32 training grant CA148724 (SSR), William and Ella Owens foundation grant (MKR) and the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio through the NCI Cancer Center Support Grant P30CA054174-17.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, UT Health Science Center, San Antonio, TX, USA

    S S Roy, V K Gonugunta, R R Tekmal & R K Vadlamudi

  2. Department of Cellular and Structural Biology, UT Health Science Center, San Antonio, TX, USA

    A Bandyopadhyay, M K Rao & L-Z Sun

  3. Cancer Therapy and Research Center, UT Health Science Center, San Antonio, TX, USA

    M K Rao, L-Z Sun, R R Tekmal & R K Vadlamudi

  4. Department of Medicine, Center for Cancer Biology, SA Pathology, School of Molecular and Biomedical science, University of Adelaide, Adelaide, South Australia, Australia

    G J Goodall

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Correspondence to R K Vadlamudi.

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Roy, S., Gonugunta, V., Bandyopadhyay, A. et al. Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer. Oncogene 33, 3707–3716 (2014). https://doi.org/10.1038/onc.2013.332

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