title: Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome.
abstract: Androgen receptor (AR) signaling in stromal cells is important in prostate cancer, yet the mechanisms underpinning stromal AR contribution to disease development and progression remain unclear. Using patient-matched benign and malignant prostate samples, we show a significant association between low AR levels in cancer associated stroma and increased prostate cancer-related death at one, three and five years post-diganosis, and in tissue recombination models with primary prostate cancer cells that low stromal AR decreases castration-induced apoptosis. AR-regulation was found to be different in primary human fibroblasts isolated from adjacent to cancerous and non-cancerous prostate epithelia, and to represent altered activation of myofibroblast pathways involved in cell cycle, adhesion, migration, and the extracellular matrix (ECM). Without AR signaling, the fibroblast-derived ECM loses the capacity to promote attachment of both myofibroblasts and cancer cells, is less able to prevent cell-matrix disruption, and is less likely to impede cancer cell invasion. AR signaling in prostate cancer stroma appears therefore to alter patient outcome by maintaining an ECM microenvironment inhibitory to cancer cell invasion. This paper provides comprehensive insight into AR signaling in the non-epithelial prostate microenvironment, and a resource from which the prognostic and therapeutic implications of stromal AR levels can be further explored.
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Damien A
authors.initials: DA
authors.lastname: Leach
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Eleanor F
authors.initials: EF
authors.lastname: Need
authors.affiliation: Department of Anatomy and Development, Monash University, VIC, Australia.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Toivanen
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Trotta
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Palethorpe
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Palenthorpe
authors.affiliation: Urology Unit, Repatriation General Hospital, SA, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tamblyn
authors.affiliation: Urology Unit, Repatriation General Hospital, SA, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Kopsaftis
authors.affiliation: Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, SA, Australia.
authors.forename: Georgina M
authors.initials: GM
authors.lastname: England
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Smith
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.|School of Nursing and Midwifery, Flinders University, Bedford Park, SA, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Drew
authors.affiliation: Urology Unit, Repatriation General Hospital, SA, Australia.
authors.forename: Carole B
authors.initials: CB
authors.lastname: Pinnock
authors.affiliation: Department of Pathology and Urology, New York University, NY, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.affiliation: Department of Anatomy and Development, Monash University, VIC, Australia.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Risbridger
authors.affiliation: Urology Unit, Repatriation General Hospital, SA, Australia.|Department of Urology, St Vincent's Hospital, Sydney and Garvan Institute, NSW, Australia.
authors.forename: Samarth
authors.initials: S
authors.lastname: Chopra
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA.
authors.forename: Donald B
authors.initials: DB
authors.lastname: DeFranco
authors.affiliation: Department of Anatomy and Development, Monash University, VIC, Australia.|Department of Physiology, Monash University, VIC, Australia.
authors.forename: Renea A
authors.initials: RA
authors.lastname: Taylor
authors.affiliation: The Basil Hetzel Institute for Translational Health Research, University of Adelaide, SA, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009919:Orchiectomy; D011379:Prognosis; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: C410798:AR protein, human; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen
keywords: androgen receptor; extracellular matrix; fibroblasts; prostate cancer; stroma