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

• Published in: Oncotarget Vol. 6; no. 14; pp. 11910 - 11929
• Main Authors: Castro, Nadia P, Fedorova-Abrams, Natalie D, Merchant, Anand S, Rangel, Maria Cristina, Nagaoka, Tadahiro, Karasawa, Hideaki, Klauzinska, Malgorzata, Hewitt, Stephen M, Biswas, Kajal, Sharan, Shyam K, Salomon, David S
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.05.2015
• Subjects: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic - metabolism; Epidermal Growth Factor - metabolism; Epithelial-Mesenchymal Transition - physiology; Female; Fluorescent Antibody Technique; Gene Knockout Techniques; Immunohistochemistry; In Situ Nick-End Labeling; Laser Capture Microdissection; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins - metabolism; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Priority Research Paper; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Notch4; epithelial-mesenchymal plasticity; triple-negative breast cancer; mouse model; Cripto-1
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4182

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.