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

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

doi:10.18632/oncotarget.4182

Nadia P Castro, Malgorzata Klauzinska + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.4182

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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.

Highlights

IntroductionBreast cancer (BC) has the highest incidence and is the second most common cause of cancer death in women in the United States [1]
Among all cancer types, breast cancer (BC) has the highest incidence and is the second most common cause of cancer death in women in the United States [1]
It is similar to the lymphatic human BC metastatic process that phenotypically and molecularly resembles the human triple-negative breast cancers (TNBC) subtype, which is associated with the poorest prognosis due to its high resistance to chemo- and radiotherapy [2]

Summary

Introduction

Breast cancer (BC) has the highest incidence and is the second most common cause of cancer death in women in the United States [1]. Basal-like or triple-negative breast cancers (TNBC), which lack expression of estrogen receptor (ER), progesterone receptor (PR) and HER2/neu tyrosine kinase receptor, are generally associated with the worst prognosis due to its high resistance to chemotherapy [2, 3]. The epithelial-mesenchymal transition (EMT) is critical during normal embryonic development, fibrosis and wound healing, and contributes to tumor invasion and metastasis [4]. Experimental evidence indicates that interconversion between EMT and the reverse process of mesenchymal-epithelial transition (MET) can occur during embryogenesis and fibrosis as well as during early stages of metastatic progression in colorectal cancer and BC, at the invasive front of primary tumors and in metastatic sites, respectively [4]

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