Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor

A. Mazumdar, R. A. Wang, S. K. Mishra, L. Adam, R. Bagheri-Yarmand, M. Mandal, R. K. Vadlamudi, R. Kumar

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Abstract

Activation of the heregulin/HER2 pathway in oestrogen receptor (ER)-positive breast-cancer cells leads to suppression of oestrogen-receptor element (ERE)-driven transcription and disruption of oestradiol responsiveness, and thus contributes to progression of tumours to more invasive phenotypes. Here we report the identification of metastatic-associated protein 1 (MTA1), a component of histone deacetylase (HDAC) and nucleosome-remodelling complexes, as a gene product induced by heregulin-β1 (HRG). Stimulation of cells with HRG is accompanied by suppression of histone acetylation and enhancement of deacetylase activity. MTA1 is also a potent corepressor of ERE transcription, as it blocks the ability of oestradiol to stimulate ER-mediated transcription. The histone-deacetylase inhibitor trichostatin A blocks MTA1-mediated repression of ERE transcription. Furthermore, MTA1 directly interacts with histone deacetylase-1 and -2 and with the activation domain of ER-α. Overexpression of MTA1 in breast-cancer cells is accompanied by enhancement of the ability of cells to invade and to grow in an anchorage-independent manner. HRG also promotes interaction of MTA1 with endogenous ER and association of MTA1 or HDAC with ERE-responsive target-gene promoters in vivo. These results identify ER-mediated transcription as a nuclear target of MTA1 and indicate that HDAC complexes associated with the MTA1 corepressor may mediate ER transcriptional repression by HRG.

Original languageEnglish (US)
Pages (from-to)30-37
Number of pages8
JournalNature Cell Biology
Volume3
Issue number1
DOIs
StatePublished - Feb 14 2001

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Mazumdar, A., Wang, R. A., Mishra, S. K., Adam, L., Bagheri-Yarmand, R., Mandal, M., Vadlamudi, R. K., & Kumar, R. (2001). Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nature Cell Biology, 3(1), 30-37. https://doi.org/10.1038/35050532