MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer

Suresh B Pakala; Suresh K Rayala; Rui-An Wang; Kazufumi Ohshiro; Prakriti Mudvari; Sirigiri Divijendra Natha Reddy; Yi Zheng; Ricardo Pires; Sandra Casimiro; M Radhakrishna Pillai; Luis Costa; Rakesh Kumar

doi:10.1158/0008-5472.CAN-12-3998

MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer

Cancer Res. 2013 Jun 15;73(12):3761-70. doi: 10.1158/0008-5472.CAN-12-3998. Epub 2013 Apr 11.

Authors

Suresh B Pakala¹, Suresh K Rayala, Rui-An Wang, Kazufumi Ohshiro, Prakriti Mudvari, Sirigiri Divijendra Natha Reddy, Yi Zheng, Ricardo Pires, Sandra Casimiro, M Radhakrishna Pillai, Luis Costa, Rakesh Kumar

Affiliation

¹ Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia 20037, USA.

Abstract

Overexpression of the prometastatic chromatin modifier protein metastasis tumor antigen 1 (MTA1) in human cancer contributes to tumor aggressiveness, but the role of endogenous MTA1 in cancer has not been explored. Here, we report the effects of selective genetic depletion of MTA1 in a physiologically relevant spontaneous mouse model of breast cancer pulmonary metastasis. We found that MTA1 acts as a mandatory modifier of breast-to-lung metastasis without effects on primary tumor formation. The underlying mechanism involved MTA1-dependent stimulation of STAT3 transcription through action on the MTA1/STAT3/Pol II coactivator complex, and, in turn, on the expression and functions of STAT3 target genes including Twist1. Accordingly, we documented a positive correlation between levels of MTA1 and STAT3 in publicly available breast cancer data sets. Together, our findings reveal an essential modifying role of the physiologic level of MTA1 in supporting pulmonary metastasis of breast cancer.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Blotting, Western
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Movement / genetics
Cells, Cultured
DNA Polymerase II / metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / secondary
Mammary Neoplasms, Animal / genetics*
Mammary Neoplasms, Animal / metabolism
Mammary Neoplasms, Animal / pathology
Mice
Mice, 129 Strain
Mice, Knockout
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Binding
RNA Interference
Repressor Proteins
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / metabolism
Trans-Activators
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism

Substances

Mta1 protein, mouse
Nuclear Proteins
Repressor Proteins
STAT3 Transcription Factor
Trans-Activators
Transcription Factors
Twist-Related Protein 1
Twist1 protein, mouse
DNA Polymerase II

Abstract

Publication types

MeSH terms

Substances

Grants and funding