Inhibitory effects of BMP9 on breast cancer cells by regulating their interaction with pre-adipocytes/adipocytes
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Ting Wang1,*, Zhihui Zhang1,*, Ke Wang2,*, Jinshu Wang1, Yayun Jiang1, Jing Xia1, Liyao Gou1, Mengyao Liu1, Lan Zhou1, Tongchuan He3, Yan Zhang1
1Key Laboratory of Diagnostic Medicine of The Chinese Ministry of Education, School of Clinical Diagnostic and Laboratory Medicine, Chongqing Medical University, Yuzhong District, Chongqing, P.R.China
2Yongchuan Hospital, Chongqing Medical University, Chongqing, P.R.China
3Molecular Oncology Laboratory, Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA
*These authors contributed equally to this work
Yan Zhang, email: [email protected]
Keywords: bone morphogenetic protein 9, adipocyte, breast cancer cell, microenvironment, leptin
Received: June 29, 2016 Accepted: March 09, 2017 Published: March 16, 2017
Bone morphogenetic protein 9 (BMP9) possesses multiple functions, but its effects on breast cancer cells in adipose microenvironment are still unclear. This study aimed to investigate whether BMP9 is able to modulate the interaction between pre-adipocytes/adipocytes and breast cancer cells. An in vitro co-culture system was established by using pre-adipocytes/adipocytes and MDA-MB-231 breast cancer cells with BMP9 over-expression. The leptin expression and leptin-induced signaling pathway were evaluated in this co-culture system. MTT assay, EdU assay and flow cytometry were used to assess the proliferation of MDA-MB-231 cells. Wound-healing assay and Transwell migration assay were used to assess the migration of MDA-MB-231 cells. Immunofluorescence staining was used to detect the expression of leptin recepter (ObR) in MDA-MB-231 cells. The expression of key molecules in leptin signaling pathway in co-culture system were detected by Western blotting. MDA-MB-231 cells and pre-adipocytes/adipocytes were inoculated into nude mice, the tumor volume was measured, and the protein expression of key molecules in leptin signaling pathway was detected. Results showed BMP9 inhibited breast tumor growth in vitro and in vivo and reduced the migration of breast cancer cells in vitro. MDA-MB-231 cells with BMP9 over-expression decreased leptin expression in pre-adipocytes/adipocytes and had reduced phosphorylation of STAT3, ERK1/2 and AKT. Taken together, our study indicates that BMP9 can inhibit the growth and metastasis of breast cancer cells, which may be related to interaction between pre-adipocytes/adipocytes and MDA-MB-231 cells via leptin signaling pathway.
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