C-C motif chemokine receptor 1 (CCR1) is a target of the EGF-AKT-mTOR-STAT3 signaling axis in breast cancer cells
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Soon Young Shin1,2, Da Hyun Lee1, Jishin Lee3, Chan Choi3, Ji-Young Kim4, Jeong-Seok Nam5, Yoongho Lim6 and Young Han Lee1,2
1Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, Republic of Korea
2Cancer and Metabolism Institute, Konkuk University, Seoul, Republic of Korea
3Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea
4Laboratory Animal Resource Center, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
5School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
6Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul, Republic of Korea
Young Han Lee, email: firstname.lastname@example.org
Soon Young Shin, email: email@example.com
Keywords: CCR1, STAT3, AKT, mTOR, metastasis
Received: June 08, 2017 Accepted: September 20, 2017 Published: October 10, 2017
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.
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