Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor.
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-beta1 (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-alpha. 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.
Mazumdar
A
A
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Wang
R A
RA
Mishra
S K
SK
Adam
L
L
Bagheri-Yarmand
R
R
Mandal
M
M
Vadlamudi
R K
RK
Kumar
R
R
D000107:Acetylation / Q000187:drug effects; D001940:Breast / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005809:Genes, Regulator / Q000187:drug effects / Q000502:physiology*; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D006657:Histones; C089320:MTA1 protein, human; D020890:Neuregulin-1; D011506:Proteins; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D015534:Trans-Activators; D006655:Histone Deacetylases