Priority Research Papers:
Cripto-1 as a novel therapeutic target for triple negative breast cancer
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Nadia P. Castro1, Natalie D. Fedorova-Abrams2, Anand S. Merchant2, Maria Cristina Rangel1, Tadahiro Nagaoka1, Hideaki Karasawa1, Malgorzata Klauzinska1, Stephen M. Hewitt3, Kajal Biswas4, Shyam K. Sharan4 and David S. Salomon1
1 Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA
2 CCRIFX Bioinformatics Core, National Cancer Institute, Bethesda, MD, USA
3 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
4 Genetics of Cancer Susceptibility Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA
David S. Salomon, email:
Nadia P. Castro, email:
Keywords: cripto-1, notch4, epithelial-mesenchymal plasticity, mouse model, triple-negative breast cancer
Received: April 17, 2015 Accepted: May 09, 2015 Published: May 19, 2014
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.
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