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A naturally occurring MTA1 variant sequesters oestrogen receptor-α in the cytoplasm

Nature volume 418, pages 654–657 (2002)Cite this article

Abstract

Oestrogen receptor (ER) is a good prognostic marker for the treatment of breast cancers. Upregulation of metastatic tumour antigen 1 (MTA1) is associated with the invasiveness and metastatic potential of several human cancers1,2 and acts as a co-repressor of nuclear ER-α3. Here we identify a naturally occurring short form of MTA1 (MTA1s) that contains a previously unknown sequence of 33 amino acids with an ER-binding motif, Leu-Arg-Ile-Leu-Leu (LRILL). MTA1s localizes in the cytoplasm, sequesters ER in the cytoplasm, and enhances non-genomic responses of ER. Deleting the LRILL motif in MTA1s abolishes its co-repressor function and its interaction with ER, and restores nuclear localization of ER. Dysregulation of human epidermal growth factor receptor-2 in breast cancer cells enhances the expression of MTA1s and the cytoplasmic sequestration of ER. Expression of MTA1s in breast cancer cells prevents ligand-induced nuclear translocation of ER and stimulates malignant phenotypes. MTA1s expression is increased in human breast tumours with no or low nuclear ER. The regulation of the cellular localization of ER by MTA1s represents a mechanism for redirecting nuclear receptor signalling by nuclear exclusion.

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Figure 1: MTA1s is a variant of MTA1.
Figure 2: MTA1s is cytoplasmic and interacts with ER.
Figure 3: MTA1s LXXLL motif required for interaction and sequestration of ER.
Figure 4: Expression of MTA1s in human breast tumours.

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Acknowledgements

We thank B. S. Katzenellenbogen and M. R. Parker for AF2 fusion protein; D. McDonnell for 3X-ERE TATA; D. Shapiro for ERE-reporter systems; D. Nguyen for cloning; and W. Schmid for the GRE-CAT promoter constructs. Susan G. Komen Breast Cancer Foundation and National Institutes of Health grants (to R.K.) supported this study.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Rakesh Kumar, Rui-An Wang, Abhijit Mazumdar, Amjad H. Talukder, Mahitosh Mandal, Zhibo Yang, Rozita Bagheri-Yarmand, Liana Adam, Christopher J. Barnes & Ratna K. Vadlamudi

  2. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Aysegul Sahin

  3. Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Gabriel Hortobagyi

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  1. Rakesh Kumar
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Correspondence to Rakesh Kumar.

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Kumar, R., Wang, RA., Mazumdar, A. et al. A naturally occurring MTA1 variant sequesters oestrogen receptor-α in the cytoplasm. Nature 418, 654–657 (2002). https://doi.org/10.1038/nature00889

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