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

Rakesh Kumar (), Rui-An Wang, Abhijit Mazumdar, Amjad H. Talukder, Mahitosh Mandal, Zhibo Yang, Rozita Bagheri-Yarmand, Aysegul Sahin, Gabriel Hortobagyi, Liana Adam, Christopher J. Barnes and Ratna K. Vadlamudi
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Rakesh Kumar: The University of Texas M. D. Anderson Cancer Center
Rui-An Wang: The University of Texas M. D. Anderson Cancer Center
Abhijit Mazumdar: The University of Texas M. D. Anderson Cancer Center
Amjad H. Talukder: The University of Texas M. D. Anderson Cancer Center
Mahitosh Mandal: The University of Texas M. D. Anderson Cancer Center
Zhibo Yang: The University of Texas M. D. Anderson Cancer Center
Rozita Bagheri-Yarmand: The University of Texas M. D. Anderson Cancer Center
Gabriel Hortobagyi: The University of Texas M. D. Anderson Cancer Center
Liana Adam: The University of Texas M. D. Anderson Cancer Center
Christopher J. Barnes: The University of Texas M. D. Anderson Cancer Center
Ratna K. Vadlamudi: The University of Texas M. D. Anderson Cancer Center

Nature, 2002, vol. 418, issue 6898, 654-657

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature00889

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