title: Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer.
abstract: The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12-CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer.
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Qinghuan
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Zhaojin
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Mi
authors.affiliation: Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Enhua
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Weifan
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Surgical Oncology, The First Afﬁliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000096:biosynthesis; D061986:MCF-7 Cells; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2