Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate.
Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here, we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly overexpressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Because the male has only one X chromosome, our data represent a paradigm of "single genetic hit" inactivation-mediated carcinogenesis.
Wang
Lizhong
L
Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109, USA.
Liu
Runhua
R
Li
Weiquan
W
Chen
Chong
C
Katoh
Hiroto
H
Chen
Guo-Yun
GY
McNally
Beth
B
Lin
Lin
L
Zhou
Penghui
P
Zuo
Tao
T
Cooney
Kathleen A
KA
Liu
Yang
Y
Zheng
Pan
P
D000818:Animals; D002478:Cells, Cultured; D041321:Chromosomes, Human, X; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011470:Prostatic Hyperplasia / Q000235:genetics; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034622:RNA Interference; D013997:Time Factors; D014158:Transcription, Genetic; D014161:Transduction, Genetic
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc