Research Papers:

Transcriptional regulation of mixed lineage kinase 3 by estrogen and its implication in ER-positive breast cancer pathogenesis

Navin Viswakarma, Rakesh Sathish Nair, Gautam Sondarva, Subhasis Das, Lucas Ibrahimi, Zhiyong Chen, Subhash Sinha, Basabi Rana and Ajay Rana _

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Oncotarget. 2017; 8:33172-33184. https://doi.org/10.18632/oncotarget.16566

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Navin Viswakarma1, Rakesh Sathish Nair1, Gautam Sondarva1, Subhasis Das1, Lucas Ibrahimi1, Zhiyong Chen4, Subhash Sinha4, Basabi Rana1,2,3, Ajay Rana1,2,3

1Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA

2University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA

3Jesse Brown VA Medical Center, Chicago, IL 60612, USA

4Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA

Correspondence to:

Ajay Rana, email: [email protected]

Keywords: estrogen receptor, MLK3, transcriptional regulation, breast cancer, estrogen response element

Received: January 30, 2017     Accepted: March 16, 2017     Published: March 25, 2017


Mixed Lineage Kinase 3 (MLK3), also called as MAP3K11 is a tightly regulated MAP3K member but its cellular function is still not fully understood. Earlier we reported post-translational regulation of MLK3 by estrogen (E2) that inhibited the kinase activity and favored survival of ER+ breast cancer cells. Here we report that MLK3 is also transcriptionally downregulated by E2 in ER+ breast cancer cells. Publicly available data and in situ hybridization of human breast tumors showed significant down regulation of MLK3 transcripts in ER+ tumors. The basal level of MLK3 transcripts and protein in ER+ breast cancer cell lines were significantly lower, and the protein expression was further down regulated by E2 in a time-dependent manner. Analysis of the promoter of MLK3 revealed two ERE sites which were regulated by E2 in ER+ but not in ER breast cancer cell lines. Both ERα and ERβ were able to bind to MLK3 promoter and recruit nuclear receptor co-repressors (NCoR, SMRT and LCoR), leading to down-regulation of MLK3 transcripts. Collectively these results suggest that recruitment of nuclear receptor co-repressor is a key feature of ligand-dependent transcriptional repression of MLK3 by ERs. Therefore coordinated transcriptional and post-translational repression of pro-apoptotic MLK3 probably is one of the mechanisms by which ER+ breast cancer cells proliferate and survive.

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