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Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor
A Mazumdar1, R A Wang, S K Mishra
1Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
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-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.
Insights
The heregulin/HER2 pathway activates metastatic-associated protein 1 (MTA1), which suppresses oestrogen receptor (ER) transcription in breast cancer. This MTA1-mediated repression contributes to tumor invasiveness.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- The heregulin/HER2 pathway promotes breast cancer progression by suppressing oestrogen receptor (ER) activity.
- Understanding the molecular mechanisms behind this ER suppression is crucial for developing targeted therapies.
Purpose of the Study:
- To identify genes induced by heregulin-beta1 (HRG) that mediate ER transcriptional suppression.
- To investigate the role of metastatic-associated protein 1 (MTA1) in ER-mediated transcription and breast cancer cell invasion.
Main Methods:
- Gene expression analysis following HRG stimulation.
- Biochemical assays to assess histone acetylation and deacetylase activity.
- Co-immunoprecipitation to study protein interactions (MTA1, HDACs, ER).
- Functional assays measuring cell invasion and anchorage-independent growth.
Main Results:
- HRG induces the expression of MTA1, a component of histone deacetylase (HDAC) complexes.
- MTA1 acts as a corepressor of ER-mediated transcription, blocking oestradiol responsiveness.
- HRG stimulation enhances HDAC activity and promotes MTA1-HDAC interaction with ER and target gene promoters.
- MTA1 overexpression enhances breast cancer cell invasion and anchorage-independent growth.
Conclusions:
- MTA1 is a key mediator of HRG-induced ER transcriptional repression in breast cancer.
- HDAC complexes associated with MTA1 play a critical role in ER transcriptional regulation by HRG.
- Targeting the MTA1/HDAC pathway may offer a therapeutic strategy for invasive ER-positive breast cancers.