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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

Prognostic value of genes overexpressed in 231-BR and ADMD-231 cellsA) Elevated expression of 231-BR overexpressed genes (TMEM47, LYPD1, CD96, TFAP2C, EEF1A2, DDX, MYH10, HOXB5, NINJ2, SERPINF1, CPE, MAGEC2, CTLA3, C17orf70, ZNF704, NCKAP1L, and TIE1) in primary breast tumor is associated with poor recurrence-free survival among patients with basal breast cancer. Patients were split by median to classify into high or low expressers. B) Elevated expression of 231-BR specific genes in luminal B breast cancer is also associated with poor recurrence-free survival. C) TMEM47 overexpression is associated with poor brain metastasis-free survival. D) Elevated expression of ADMD-231 overexpressed genes (CYB5R2, TAGLN, HAND1, RAB3IL1, TRMT12, TSPAN8, MMP3, STXBP6, AP1S2, and HSPB8) in primary tumor is associated poor recurrence-free survival among patients with basal breast cancer. E) ADMD-231 overexpressed genes are also associated with poor distant metastasis-free survival among patients with basal breast cancer.
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Figure 2: Prognostic value of genes overexpressed in 231-BR and ADMD-231 cellsA) Elevated expression of 231-BR overexpressed genes (TMEM47, LYPD1, CD96, TFAP2C, EEF1A2, DDX, MYH10, HOXB5, NINJ2, SERPINF1, CPE, MAGEC2, CTLA3, C17orf70, ZNF704, NCKAP1L, and TIE1) in primary breast tumor is associated with poor recurrence-free survival among patients with basal breast cancer. Patients were split by median to classify into high or low expressers. B) Elevated expression of 231-BR specific genes in luminal B breast cancer is also associated with poor recurrence-free survival. C) TMEM47 overexpression is associated with poor brain metastasis-free survival. D) Elevated expression of ADMD-231 overexpressed genes (CYB5R2, TAGLN, HAND1, RAB3IL1, TRMT12, TSPAN8, MMP3, STXBP6, AP1S2, and HSPB8) in primary tumor is associated poor recurrence-free survival among patients with basal breast cancer. E) ADMD-231 overexpressed genes are also associated with poor distant metastasis-free survival among patients with basal breast cancer.

Mentions: Analysis of a public database [35], which contains gene expression data in on primary tumors but not metastases, for the prognostic value of combined expression of the top 17 genes overexpressed (> 2 fold, p<0.0001, TMEM47, LYPD1, CD96, TFAP2C, EEF1A2, DDX, MYH10, HOXB5, NINJ2, SERPINF1, CPE, MAGEC2, CTLA3, C17orf70, ZNF704, NCKAP1L and TIE1) in 231-BR cells for which data were available showed elevated expression correlating with poor recurrence-free survival of patients with basal or luminal B breast cancer (Figure 2A and 2B). With respect to brain metastasis-free survival, overexpression of TMEM47 was associated with poor brain metastasis-free survival [20] (Figure 2C). TMEM47 displayed prognostic value in estrogen receptor and progesterone negative but not in estrogen receptor and progesterone receptor positive breast cancer (data not shown). LYPD1 and SLITRK2 did not show any significance.


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)

Prognostic value of genes overexpressed in 231-BR and ADMD-231 cellsA) Elevated expression of 231-BR overexpressed genes (TMEM47, LYPD1, CD96, TFAP2C, EEF1A2, DDX, MYH10, HOXB5, NINJ2, SERPINF1, CPE, MAGEC2, CTLA3, C17orf70, ZNF704, NCKAP1L, and TIE1) in primary breast tumor is associated with poor recurrence-free survival among patients with basal breast cancer. Patients were split by median to classify into high or low expressers. B) Elevated expression of 231-BR specific genes in luminal B breast cancer is also associated with poor recurrence-free survival. C) TMEM47 overexpression is associated with poor brain metastasis-free survival. D) Elevated expression of ADMD-231 overexpressed genes (CYB5R2, TAGLN, HAND1, RAB3IL1, TRMT12, TSPAN8, MMP3, STXBP6, AP1S2, and HSPB8) in primary tumor is associated poor recurrence-free survival among patients with basal breast cancer. E) ADMD-231 overexpressed genes are also associated with poor distant metastasis-free survival among patients with basal breast cancer.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Prognostic value of genes overexpressed in 231-BR and ADMD-231 cellsA) Elevated expression of 231-BR overexpressed genes (TMEM47, LYPD1, CD96, TFAP2C, EEF1A2, DDX, MYH10, HOXB5, NINJ2, SERPINF1, CPE, MAGEC2, CTLA3, C17orf70, ZNF704, NCKAP1L, and TIE1) in primary breast tumor is associated with poor recurrence-free survival among patients with basal breast cancer. Patients were split by median to classify into high or low expressers. B) Elevated expression of 231-BR specific genes in luminal B breast cancer is also associated with poor recurrence-free survival. C) TMEM47 overexpression is associated with poor brain metastasis-free survival. D) Elevated expression of ADMD-231 overexpressed genes (CYB5R2, TAGLN, HAND1, RAB3IL1, TRMT12, TSPAN8, MMP3, STXBP6, AP1S2, and HSPB8) in primary tumor is associated poor recurrence-free survival among patients with basal breast cancer. E) ADMD-231 overexpressed genes are also associated with poor distant metastasis-free survival among patients with basal breast cancer.
Mentions: Analysis of a public database [35], which contains gene expression data in on primary tumors but not metastases, for the prognostic value of combined expression of the top 17 genes overexpressed (> 2 fold, p<0.0001, TMEM47, LYPD1, CD96, TFAP2C, EEF1A2, DDX, MYH10, HOXB5, NINJ2, SERPINF1, CPE, MAGEC2, CTLA3, C17orf70, ZNF704, NCKAP1L and TIE1) in 231-BR cells for which data were available showed elevated expression correlating with poor recurrence-free survival of patients with basal or luminal B breast cancer (Figure 2A and 2B). With respect to brain metastasis-free survival, overexpression of TMEM47 was associated with poor brain metastasis-free survival [20] (Figure 2C). TMEM47 displayed prognostic value in estrogen receptor and progesterone negative but not in estrogen receptor and progesterone receptor positive breast cancer (data not shown). LYPD1 and SLITRK2 did not show any significance.

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