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, Harikrishna Nakshatri

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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 brainmetastasis (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 organspecific metastasis and could potentially be targeted therapeutically.

Original languageEnglish (US)
Pages (from-to)12682-12696
Number of pages15
JournalOncotarget
Volume6
Issue number14
DOIs
StatePublished - 2015

Keywords

  • Brain metastasis
  • Breast cancer
  • DMAPT
  • NF-kB
  • TMEM47

ASJC Scopus subject areas

  • Oncology

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