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

Burnett RM, Craven KE, Krishnamurthy P, Goswami CP, Badve S, Crooks P, Mathews WP, Bhat-Nakshatri P, Nakshatri H - Oncotarget (2015)

Bottom Line: 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.We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

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 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.

No MeSH data available.


Related in: MedlinePlus

Ingenuity pathway analysis of genes differentially expressed in ADMD-231 cellsA) Notch, FXR/RXR and LXR/RXR networks involved in steroidogenesis similar to adrenal gland are the major pathways in ADMD-231 cells. B) ADMD-231 cells show activation of Notch-ERK-AKT network. C) NF-κB signaling network is active in ADMD-231 cells.
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Figure 4: Ingenuity pathway analysis of genes differentially expressed in ADMD-231 cellsA) Notch, FXR/RXR and LXR/RXR networks involved in steroidogenesis similar to adrenal gland are the major pathways in ADMD-231 cells. B) ADMD-231 cells show activation of Notch-ERK-AKT network. C) NF-κB signaling network is active in ADMD-231 cells.

Mentions: To determine the signaling pathways active in cells isolated from different sites of metastasis, we subjected differentially expressed genes to Ingenuity pathway analysis. Glutathione-mediated detoxification, NRF2-mediated oxidative stress response, and Semaphorin signaling in neurons are a few of the signaling pathways in 231-BR cells (Figure 3A). The top two networks in 231-BR cells included SRC-ERK-growth hormone and NF-κB (Figure 3B and 3C). SRC pathway activation has also been noted previously in the BT474 HER2-positive cell brain metastasis model [18]. Notch, LXR/RXR and FXR/RXR pathways are the three major pathways activated in ADMD-231 cells (Figure 4A). Networks in these cells included Notch-ERK-AKT and NF-κB (Figure 4B and 4C).


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

Burnett RM, Craven KE, Krishnamurthy P, Goswami CP, Badve S, Crooks P, Mathews WP, Bhat-Nakshatri P, Nakshatri H - Oncotarget (2015)

Ingenuity pathway analysis of genes differentially expressed in ADMD-231 cellsA) Notch, FXR/RXR and LXR/RXR networks involved in steroidogenesis similar to adrenal gland are the major pathways in ADMD-231 cells. B) ADMD-231 cells show activation of Notch-ERK-AKT network. C) NF-κB signaling network is active in ADMD-231 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494966&req=5

Figure 4: Ingenuity pathway analysis of genes differentially expressed in ADMD-231 cellsA) Notch, FXR/RXR and LXR/RXR networks involved in steroidogenesis similar to adrenal gland are the major pathways in ADMD-231 cells. B) ADMD-231 cells show activation of Notch-ERK-AKT network. C) NF-κB signaling network is active in ADMD-231 cells.
Mentions: To determine the signaling pathways active in cells isolated from different sites of metastasis, we subjected differentially expressed genes to Ingenuity pathway analysis. Glutathione-mediated detoxification, NRF2-mediated oxidative stress response, and Semaphorin signaling in neurons are a few of the signaling pathways in 231-BR cells (Figure 3A). The top two networks in 231-BR cells included SRC-ERK-growth hormone and NF-κB (Figure 3B and 3C). SRC pathway activation has also been noted previously in the BT474 HER2-positive cell brain metastasis model [18]. Notch, LXR/RXR and FXR/RXR pathways are the three major pathways activated in ADMD-231 cells (Figure 4A). Networks in these cells included Notch-ERK-AKT and NF-κB (Figure 4B and 4C).

Bottom Line: 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.We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

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 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.

No MeSH data available.


Related in: MedlinePlus