C-C motif chemokine receptor 1 (CCR1) is a target of the EGF-AKT-mTOR-STAT3 signaling axis in breast cancer cells.

Soon Young Shin,Chan Choi,Young Han Lee,Jeong-Seok Nam,Yoongho Lim,Jishin Lee,Ji-Young Kim,Da Hyun Lee

doi:10.18632/oncotarget.21813

Abstract

The CC motif chemokine receptor 1 (CCR1) has been implicated in tumor invasion and metastasis in numerous cancers. However, the detailed mechanism of CCR1 upregulation in metastatic tumor cells is poorly understood. The aim of this study was to clarify the regulatory mechanism underlying transcriptional activation of the CCR1 gene in response to epidermal growth factor (EGF) stimulation in breast cancer cells. CCR1 was highly expressed in human breast invasive ductal carcinoma (IDC) compared to adjacent normal tissues. Upon EGF stimulation, CCR1 expression was upregulated at the transcriptional level. Promoter analysis showed that signal transducer and activator of transcription 3 (STAT3) is necessary for EGF-induced CCR1 promoter activation, and STAT3 silencing abrogated EGF-induced CCR1 transcription. Pharmacological inhibition and short hairpin RNA-mediated knockdown experiments showed that AKT-dependent mammalian target of rapamycin (mTOR) activation was involved in the phosphorylation of serine-727 of STAT3, which in turn stimulated the transcription of the CCR1 gene. In conclusion, the AKT-mTOR-STAT3 signaling axis contributes to EGF-induced CCR1 expression, which promotes invasion and metastasis in breast cancer cells. We propose that the AKT-mTOR-STAT3 axis is a potential therapeutic target for blocking the invasion and metastasis of breast cancers.

Highlights

Metastasis is the spread of cancer cells from the original tumor to other sites of the body through the tumor vasculature and lymphatics; for most solid tumors, it is the major cause of death
Pharmacological inhibition and short hairpin RNA-mediated knockdown experiments showed that AKT-dependent mammalian target of rapamycin activation was involved in the phosphorylation of serine-727 of signal transducer and activator of transcription 3 (STAT3), which in turn stimulated the transcription of the chemokine receptor 1 (CCR1) gene
We found that the CCR1 immunoreactivity was stronger in invasive ductal carcinoma (IDC) than in adjacent normal tissues (Figure 1A)

Summary

Introduction

Metastasis is the spread of cancer cells from the original tumor to other sites of the body through the tumor vasculature and lymphatics; for most solid tumors, it is the major cause of death. The tumor microenvironment comprises infiltrating immune cells, endothelial cells, and stromal fibroblasts, which may provide the growth factors and cytokines that promote tumor growth, survival, and invasion [1]. Stromal cells and cancer cells produce various chemokines that control tumor growth and progression [2,3,4], and emerging www.impactjournals.com/oncotarget evidence shows that a variety of chemokine receptors are highly expressed on tumor cells and involved in tumor growth and metastasis [1, 4, 5]. In human breast cancer cells, chemokine receptors such as CXC chemokine receptor 4 (CXCR4) and CC motif chemokine receptor 7 (CCR7) are overexpressed and are involved in chemotactic and invasive responses [1, 5]

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