CSF-1/CSF-1R axis is associated with epithelial/mesenchymal hybrid phenotype in epithelial-like inflammatory breast cancer

Kazuharu Kai,Dongwei Zhang,Arvind Rao,Alastair Thompson,Yuko Takahashi,Naoto T Ueno,Subrata Sen,Takayuki Iwamoto,Li Shen

doi:10.1038/s41598-018-27409-x

Abstract

Inflammatory breast cancer (IBC) is a rare subtype of breast cancer, accounting for 8–10% of breast cancer-associated deaths in the US. Clinical hallmarks of IBC include tumor emboli in lymphatic vessels and E-cadherin overexpression, which supports a type of metastasis referred to as cell cluster-based metastasis, prevalent in IBC. In contrast, we previously reported epithelial-to-mesenchymal transition (EMT)-based progression of IBC, utilizing in vivo xenografts and in vitro Matrigel culture models. To address these two contradictory concepts of IBC metastasis, we used Matrigel culture to induce EMT in a panel of IBC cells. Results revealed Matrigel culture induced vimentin expression in SUM149 and SUM190 IBC cells at the transcriptional and protein levels while maintaining the expression of E-cadherin, a phenomenon referred to as partial EMT. Transcriptional profiling revealed that expression of colony-stimulating factor 1 (CSF-1) was induced in Matrigel culture. When the receptor tyrosine kinase of CSF-1 (CSF-1R) was inhibited by CSF-1R inhibitor BLZ945, the partial EMT was reversed in a dose-dependent manner, indicating that the CSF-1/CSF-1R axis plays a key role in controlling partial EMT. This observation may help reconcile the two contradictory theories of IBC metastasis, EMT vs cell cluster-based metastasis.

Highlights

Inflammatory breast cancer (IBC) is a rare subtype of breast cancer, accounting for only 2% of all new breast cancer cases, but a clinically dismal disease responsible for 8–10% of all breast cancer-related deaths in the US1,2
We found that SUM149 and SUM190 IBC cells transitioned from an E to E/M phenotype with the induction of colony-stimulating factor 1 (CSF-1) expression in Matrigel culture
Following treatment with BLZ945, an inhibitor of the CSF-1R, the partial epithelial-to-mesenchymal transition (EMT) was reversed in a dose-dependent manner

Summary

Introduction

Inflammatory breast cancer (IBC) is a rare subtype of breast cancer, accounting for only 2% of all new breast cancer cases, but a clinically dismal disease responsible for 8–10% of all breast cancer-related deaths in the US1,2. Tumor emboli are composed of clustered IBC cells that express high levels of E-cadherin, a molecule critical for intercellular adhesion Given this evidence, IBC’s spread has been suggested to occur through collective invasion, a type of invasion in which cancer cells maintain their attachment to each other rather than invading as solitary cells, and undergo cell cluster-based metastasis by maintaining expression of E-cadherin through the entire process. In vivo metastasis and EMT were inhibited by erlotinib, an inhibitor of epidermal growth factor receptor (EGFR), a molecule known to drive EMT depending on the type of cells, even though the erlotinib dose used in this experiment did not inhibit cell growth It appears that a transient EMT induction plays a role in promoting IBC metastasis, at least in some instances, as reflected in the SUM149 model. Therapeutic targeting of the CSF-1/CSF-1R axis, appears to be a rational approach for treatment of these IBC cases and warrants further investigation in clinical settings

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