title: Cripto-1 as a novel therapeutic target for triple negative breast cancer.
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.
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Castro
authors.affiliation: CCRIFX Bioinformatics Core, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Fedorova-Abrams
authors.affiliation: CCRIFX Bioinformatics Core, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Anand S
authors.initials: AS
authors.lastname: Merchant
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rangel
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nagaoka
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karasawa
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Klauzinska
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Genetics of Cancer Susceptibility Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Kajal
authors.initials: K
authors.lastname: Biswas
authors.affiliation: Genetics of Cancer Susceptibility Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
authors.affiliation: Tumor Growth Factor Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D061346:Laser Capture Microdissection; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C489450:Tdgf1 protein, mouse; D004815:Epidermal Growth Factor
keywords: Cripto-1; Notch4; epithelial-mesenchymal plasticity; mouse model; triple-negative breast cancer