Research Papers:

Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells

Riesa M. Burnett, Kelly E. Craven, Purna Krishnamurthy, Chirayu P. Goswami, Sunil Badve, Peter Crooks, William P. Mathews, Poornima Bhat-Nakshatri and Harikrishna Nakshatri _

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Oncotarget. 2015; 6:12682-12696. https://doi.org/10.18632/oncotarget.3707

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Riesa M. Burnett1, Kelly E. Craven2, Purna Krishnamurthy1, Chirayu P. Goswami4, Sunil Badve3, Peter Crooks5, William P. Mathews6, Poornima Bhat-Nakshatri1 and Harikrishna Nakshatri1,2,4

1 Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

3 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

4 Department of Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA

5 University of Arkansas, Little Rock, AR, USA

6 Leuchemix, Inc., Woodside, CA, USA

Correspondence to:

Harikrishna Nakshatri, email:

Keywords: breast cancer, brain metastasis, NF-kB, DMAPT, TMEM47

Received: December 31, 2014 Accepted: March 10, 2015 Published: March 30, 2015


Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. Neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 were specifically overexpressed in 231-BR cells. Pathway-analyses revealed activation of signaling networks that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all except BMD-231 cells. We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR). Dimethylaminoparthenolide inhibited NF-κB activity, LYPD1 expression, and proliferation of 231-BR and 4T1-BR cells. Thus, transcriptome change enabling adaptation to host organs is likely one of the mechanisms associated with organ-specific metastasis and could potentially be targeted therapeutically.

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