SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation.
Dysregulation of tissue development pathways can contribute to cancer initiation and progression. In murine embryonic prostate epithelia, the transcription factor SOX9 is required for proper prostate development. In this study, we examined a role for SOX9 in prostate cancer in mouse and human. In Pten and Nkx3.1 mutant mice, cells with increased levels of SOX9 appeared within prostate epithelia at early stages of neoplasia, and higher expression correlated with progression at all stages of disease. In transgenic mice, SOX9 overexpression in prostate epithelia increased cell proliferation without inducing hyperplasia. In transgenic mice that were also heterozygous for mutant Pten, SOX9 overexpression quickened the induction of high-grade prostate intraepithelial neoplasia. In contrast, Sox9 attenuation led to a decrease proliferating prostate epithelia cells in normal and homozygous Pten mutant mice with prostate neoplasia. Analysis of a cohort of 880 human prostate cancer samples showed that SOX9 expression was associated with increasing Gleason grades and higher Ki67 staining. Our findings identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation.
Thomsen
Martin K
MK
Section of Gene Function and Regulation, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Ambroisine
Laurence
L
Wynn
Sarah
S
Cheah
Kathryn S E
KS
Foster
Christopher S
CS
Fisher
Gabrielle
G
Berney
Daniel M
DM
Møller
Henrik
H
Reuter
Victor E
VE
Scardino
Peter
P
Cuzick
Jack
J
Ragavan
Narasimhan
N
Singh
Paras B
PB
Martin
Francis L
FL
Butler
Christopher M
CM
Cooper
Colin S
CS
Swain
Amanda
A
D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; C102837:Nkx3-1 protein, mouse; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase