title: IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer.
abstract: Cancer-associated fibroblasts (CAFs) have been implicated in the development of resistance to anticancer drugs; however, the role and mechanism underlying CAFs in luminal breast cancer (BrCA) tamoxifen resistance are unclear. We found that stromal fibroblasts isolated from the central or peripheral area of BrCA have similar CAF phenotype and activity. In vitro and in vivo experiments showed that CAFs derived from clinical-luminal BrCAs induce tamoxifen resistance through decreasing estrogen receptor-α (ER-α) level when cultured with luminal BrCA cell lines MCF7 and T47D. CAFs promoted tamoxifen resistance through interleukin-6 (IL-6) secretion, which activates Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells, followed by induction of epithelial-mesenchymal transition and upregulation of E3 ubiquitin ligase anaphase-promoting complex 10 activity, which targeted ER-α degradation through the ubiquitin-proteasome pathway. Inhibition of proteasome activity, IL-6 activity or either the JAK/STAT3 or PI3K/AKT pathways markedly reduced CAF-induced tamoxifen resistance. In xenograft experiments of CAFs mixed with MCF7 cells, CAF-specific IL-6 knockdown inhibited tumorigenesis and restored tamoxifen sensitivity. These findings indicate that CAFs mediate tamoxifen resistance through IL-6-induced degradation of ER-α in luminal BrCAs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.158.
authors.affiliation: Department of Biochemistry and Molecular and Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.affiliation: Comprehensive Breast Health Center, Shanghai Jiaotong University School of Medicine, Ruijin Hospital, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Biochemistry and Molecular and Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular and Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Zu
authors.affiliation: Department of Biochemistry and Molecular and Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Hao
authors.affiliation: Department of Biochemistry and Molecular and Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Comprehensive Breast Health Center, Shanghai Jiaotong University School of Medicine, Ruijin Hospital, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Qu
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cui
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Keller
authors.affiliation: Comprehensive Breast Health Center, Shanghai Jiaotong University School of Medicine, Ruijin Hospital, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Comprehensive Breast Health Center, Shanghai Jiaotong University School of Medicine, Ruijin Hospital, Shanghai, China.
authors.forename: K
authors.initials: K
authors.lastname: Shen
authors.affiliation: 1] Department of Biochemistry and Molecular and Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] Comprehensive Breast Health Center, Renji Hospital, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang