BRAF activation initiates but does not maintain invasive prostate adenocarcinoma.
Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)--a mutation found in approximately 10% of human prostate tumors--was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance.
Jeong
Joseph H
JH
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
Wang
Zhenxiong
Z
Guimaraes
Alexander S
AS
Ouyang
Xuesong
X
Figueiredo
Jose L
JL
Ding
Zhihu
Z
Jiang
Shan
S
Guney
Isil
I
Kang
Gyeong Hoon
GH
Shin
Eyoung
E
Hahn
William C
WC
Loda
Massimo F
MF
Abate-Shen
Cory
C
Weissleder
Ralph
R
Chin
Lynda
L
D000728:Androgens; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002369:Castration; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism; D011467:Prostate / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes; D019459:Urothelium / Q000196:embryology / Q000473:pathology
D000728:Androgens; D014408:Biomarkers, Tumor; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt