Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells.
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.
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Riesa M
RM
Burnett
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Kelly E
KE
Craven
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Purna
P
Krishnamurthy
Department of Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Chirayu P
CP
Goswami
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Sunil
S
Badve
University of Arkansas, Little Rock, AR, USA.
Peter
P
Crooks
Leuchemix, Inc., Woodside, CA, USA.
William P
WP
Mathews
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Poornima
P
Bhat-Nakshatri
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
Harikrishna
H
Nakshatri
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome
DMAPT; NF-kB; TMEM47; brain metastasis; breast cancer