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

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.

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Figure 1: HRG regulation of MTA1 expression.
Figure 2: HRG regulation of HDAC activity.
Figure 3: MTA1 represses ERE-mediated transcription.
Figure 4: MTA1 regulation of the function of the ER AF2 domain.
Figure 5: Direct association of MTA1 with HDACs and ER.
Figure 6: Characterization of MCF-7 cells overexpressing MTA1.
Figure 7: HRG promotes interaction of MTA1 with the endogenous ER pathway.
Figure 8: MTA1 expression during embryogenesis and mammary-gland development.

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Acknowledgements

We thank D. Allies for anti-acetylated H4 antibody, D. McDonnell for 3X-ERE TATA, P. Leder for heregulin transgenic mice, F. Claret for 5XGAL4, W. Wang for Gal4–MTA1 and anti-CHD4 antibody, D. Shapiro for ERE-reporter systems, M. R. Parker for AF1 and AF2 fusion-protein expression vectors, E. Seto for HDACs expression vectors, S. Roth for HDAC assay substrate and useful tips, D. Stern for HER2 constructs, M-C. Hung for the Gal4 system, W. Schmid for GRE–CAT promoter constructs, R. Kleene for anti-MTA1 antibody, and D. Reinberg for anti-MTA2 antibody. This study was supported by NIH grants CA80066, CA65746 and CA84456, by the Breast Cancer Research Program of The University of Texas M. D. Anderson Cancer Center (to R.K.), and by Cancer Center Core grant CA16672.

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Correspondence to Rakesh Kumar.

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Figure S1

MTAI1 act as a global steroidal repressor. (PDF 20 kb)

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Mazumdar, A., Wang, RA., Mishra, S. et al. Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. Nat Cell Biol 3, 30–37 (2001). https://doi.org/10.1038/35050532

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