title: Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling.
abstract: Androgen receptor (AR) signaling is important for prostate cancer progression. However, androgen-deprivation and/or AR targeting-based therapies often lead to resistance. Here, we demonstrate that loss of AR expression results in STAT3 activation in prostate cancer cells. AR downregulation further leads to development of prostate cancer stem-like cells (CSC), which requires STAT3. In human prostate tumor tissues, elevated cancer stem-like cell markers coincide with those cells exhibiting high STAT3 activity and low AR expression. AR downregulation-induced STAT3 activation is mediated through increased interleukin (IL)-6 expression. Treating mice with soluble IL-6 receptor fusion protein or silencing STAT3 in tumor cells significantly reduced prostate tumor growth and CSCs. Together, these findings indicate an opposing role of AR and STAT3 in prostate CSC development.
authors.affiliation: Authors' Affiliations: Departments of Molecular Medicine, Cancer Immunotherapy and Tumor Immunology, and Medical Oncology, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California; and Institute for Biochemistry and Molecular Biology, Universitätsklinikum RWTH Aachen, Aachen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schroeder
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Gregory
authors.initials: G
authors.lastname: Cherryholmes
authors.forename: Claudia
authors.initials: C
authors.lastname: Kowolik
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.forename: Sumanta
authors.initials: S
authors.lastname: Pal
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller-Newen
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor