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EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer
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EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer
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Journal Article
EGFR inhibition blocks cancer stem cell clustering and lung metastasis of triple negative breast cancer
2021
Overview
Triple-negative breast cancer (TNBC) is one of the most aggressive and metastatic breast cancer subtypes lacking targeted therapy. Our recent work demonstrated that circulating tumor cell (CTC) clusters and polyclonal metastasis of TNBC are driven by aggregation of CD44
cancer stem cells (CSC) and associated with an unfavorable prognosis, such as low overall survival. However, there is no existing therapeutic that can specifically block CTC or CSC cluster formation.
Using patient-derived xenograft (PDX) models, we established an
tumor cell clustering assay for a pilot screening of blockade antibodies. After identifying EGFR as a target candidate, we modulated the gene expression and inhibited its kinase activity to determine its functional importance in tumor cell clustering and therapeutic inhibition of lung metastasis. We also examined the molecular regulation network of EGFR and a potential connection to CSC marker CD44 and microRNAs, which regulate CTC clustering.
We report here that EGFR inhibition successfully blocks circulating CSC (cCSC) clustering and lung metastasis of TNBC. EGFR enhances CD44-mediated tumor cell aggregation and CD44 stabilizes EGFR. Importantly, blocking EGFR by a novel anti-EGFR monoclonal antibody (clone LA1) effectively blocked cell aggregation
and reduced lung metastasis
. Furthermore, our data demonstrated that the tumor suppressor microRNA-30c serves as another negative regulator of cCSC clustering and lung metastasis by targeting CD44 as well as its downstream effector EGFR.
Our studies identify a novel anti-EGFR therapeutic strategy to inhibit cCSC aggregation and therefore abolish cCSC cluster-mediated metastasis of TNBC.
Publisher
Ivyspring International Publisher,Ivyspring International Publisher Pty Ltd
Subject
/ Antineoplastic Agents - therapeutic use
/ Antineoplastic Agents, Immunological
/ Antineoplastic Agents, Immunological - immunology
/ Antineoplastic Agents, Immunological - therapeutic use
/ Cell Aggregation - drug effects
/ Cloning
/ ErbB Receptors - antagonists & inhibitors
/ Erlotinib Hydrochloride - therapeutic use
/ Female
/ Humans
/ Hyaluronan Receptors - antagonists & inhibitors
/ Hyaluronan Receptors - physiology
/ Kinases
/ Lung Neoplasms - prevention & control
/ Lungs
/ Mice
/ Neoplasm Proteins - antagonists & inhibitors
/ Neoplasm Proteins - physiology
/ Neoplastic Cells, Circulating
/ Neoplastic Cells, Circulating - drug effects
/ Neoplastic Stem Cells - drug effects
/ RNA
/ Triple Negative Breast Neoplasms
/ Triple Negative Breast Neoplasms - drug therapy
