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Cripto-1 as a novel therapeutic target for triple negative breast cancer.

Castro NP, Fedorova-Abrams ND, Merchant AS, Rangel MC, Nagaoka T, Karasawa H, Klauzinska M, Hewitt SM, Biswas K, Sharan SK, Salomon DS - Oncotarget (2015)

Bottom Line: The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively.Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis.Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC.

View Article: PubMed Central - PubMed

Affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.

ABSTRACT
Triple-negative breast cancer (TNBC) presents the poorest prognosis among the breast cancer subtypes and no current standard therapy. Here, we performed an in-depth molecular analysis of a mouse model that establishes spontaneous lung metastasis from JygMC(A) cells. These primary tumors resembled the triple-negative breast cancer (TNBC) both phenotypically and molecularly. Morphologically, primary tumors presented both epithelial and spindle-like cells but displayed only adenocarcinoma-like features in lung parenchyma. The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively. Cripto-1, an embryonic stem cell marker, was present in spindle-like areas and its promoter showed activity in primary tumors. Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis. Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC.

No MeSH data available.


Related in: MedlinePlus

Relevant pathways, gene and protein expression in primary tumors and lung metastasis and similarities with human breast cancerEnriched pathways in primary mammary tumors. B. Enriched pathways in lung metastasis. C. Common seven genes between Nanostring and microarray analysis D. BMP4 and CDH1 protein expression. E. Differentially expressed genes between JygMC(A) primary mammary tumors and/or lung metastasis and human breast cancer subtypes and/or metastasis datasets.
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Figure 4: Relevant pathways, gene and protein expression in primary tumors and lung metastasis and similarities with human breast cancerEnriched pathways in primary mammary tumors. B. Enriched pathways in lung metastasis. C. Common seven genes between Nanostring and microarray analysis D. BMP4 and CDH1 protein expression. E. Differentially expressed genes between JygMC(A) primary mammary tumors and/or lung metastasis and human breast cancer subtypes and/or metastasis datasets.

Mentions: To fully characterize gene expression patterns of the JygMC(A) model on a global scale, we performed whole-genome transcriptome microarray profiling of primary mammary tumors, lung metastases, NMG and normal lung parenchyma. Differential expression analysis (FDR adjusted p-value <0.05 and fold change (FC)>= 2) identified 2,915 genes between primary tumors and NMG including 1,089 up-regulated and 1,826 down-regulated genes (Dataset S2A). Additionally, we identified 472 genes differentially expressed between lung metastases and primary tumors including 430 up-regulated and 42 down-regulated genes (Dataset S2B). A four-way Venn diagram shows increases and decreases of expressed genes for both comparisons (Figure S1B). Using the top 1,000 differentially expressed genes (FDR adjusted p-value <0.05 and FC>=3), we identified eight pathways enriched in primary tumors as compared to NMG samples, such as cytokine-cytokine receptor and cell adhesion molecules (Figure 4A), and ten pathways enriched in the lung metastases as compared to the primary tumors, such as the integrin signaling pathway, chemokine-mediated inflammation and the cytokine signaling pathway (Figure 4B). A complete list of the pathways and genes involved are summarized in Dataset S2C and S2D, respectively.


Cripto-1 as a novel therapeutic target for triple negative breast cancer.

Castro NP, Fedorova-Abrams ND, Merchant AS, Rangel MC, Nagaoka T, Karasawa H, Klauzinska M, Hewitt SM, Biswas K, Sharan SK, Salomon DS - Oncotarget (2015)

Relevant pathways, gene and protein expression in primary tumors and lung metastasis and similarities with human breast cancerEnriched pathways in primary mammary tumors. B. Enriched pathways in lung metastasis. C. Common seven genes between Nanostring and microarray analysis D. BMP4 and CDH1 protein expression. E. Differentially expressed genes between JygMC(A) primary mammary tumors and/or lung metastasis and human breast cancer subtypes and/or metastasis datasets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494913&req=5

Figure 4: Relevant pathways, gene and protein expression in primary tumors and lung metastasis and similarities with human breast cancerEnriched pathways in primary mammary tumors. B. Enriched pathways in lung metastasis. C. Common seven genes between Nanostring and microarray analysis D. BMP4 and CDH1 protein expression. E. Differentially expressed genes between JygMC(A) primary mammary tumors and/or lung metastasis and human breast cancer subtypes and/or metastasis datasets.
Mentions: To fully characterize gene expression patterns of the JygMC(A) model on a global scale, we performed whole-genome transcriptome microarray profiling of primary mammary tumors, lung metastases, NMG and normal lung parenchyma. Differential expression analysis (FDR adjusted p-value <0.05 and fold change (FC)>= 2) identified 2,915 genes between primary tumors and NMG including 1,089 up-regulated and 1,826 down-regulated genes (Dataset S2A). Additionally, we identified 472 genes differentially expressed between lung metastases and primary tumors including 430 up-regulated and 42 down-regulated genes (Dataset S2B). A four-way Venn diagram shows increases and decreases of expressed genes for both comparisons (Figure S1B). Using the top 1,000 differentially expressed genes (FDR adjusted p-value <0.05 and FC>=3), we identified eight pathways enriched in primary tumors as compared to NMG samples, such as cytokine-cytokine receptor and cell adhesion molecules (Figure 4A), and ten pathways enriched in the lung metastases as compared to the primary tumors, such as the integrin signaling pathway, chemokine-mediated inflammation and the cytokine signaling pathway (Figure 4B). A complete list of the pathways and genes involved are summarized in Dataset S2C and S2D, respectively.

Bottom Line: The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively.Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis.Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC.

View Article: PubMed Central - PubMed

Affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.

ABSTRACT
Triple-negative breast cancer (TNBC) presents the poorest prognosis among the breast cancer subtypes and no current standard therapy. Here, we performed an in-depth molecular analysis of a mouse model that establishes spontaneous lung metastasis from JygMC(A) cells. These primary tumors resembled the triple-negative breast cancer (TNBC) both phenotypically and molecularly. Morphologically, primary tumors presented both epithelial and spindle-like cells but displayed only adenocarcinoma-like features in lung parenchyma. The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively. Cripto-1, an embryonic stem cell marker, was present in spindle-like areas and its promoter showed activity in primary tumors. Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis. Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC.

No MeSH data available.


Related in: MedlinePlus