Oncotarget

Priority Research Papers:

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

Nadia P. Castro, Natalie D. Fedorova-Abrams, Anand S. Merchant, Maria Cristina Rangel, Tadahiro Nagaoka, Hideaki Karasawa, Malgorzata Klauzinska, Stephen M. Hewitt, Kajal Biswas, Shyam K. Sharan and David S. Salomon _

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Oncotarget. 2015; 6:11910-11929. https://doi.org/10.18632/oncotarget.4182

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Abstract

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

Correspondence to:

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

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.


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