Comprehensive mutational analysis and mRNA isoform quantification of TP63 in normal and neoplastic human prostate cells.
BACKGROUND
The role of TP63 in cancer remains controversial since both oncogenic and tumor suppressive actions have been reported. p63 protein is found in the nuclei of basal cells of the normal prostate, yet it is absent in the vast majority of prostate cancer nuclei. Since a complex array of TP63 mRNA transcripts encode polypeptides with distinct functional properties, it is important to determine which forms are expressed in normal and prostate cancer tissue.


METHODS
We used real-time RT-PCR to distinguish TP63 mRNA isoforms in prostate cancer cell lines (n = 7), and samples from prostate cancer patients. We sequenced all TP63 exons from 20 primary tumors, 20 metastases, 28 tumor xenografts, and 7 prostate cancer cell lines.


RESULTS
TP63 mRNA isoforms were present in all tumors, albeit at levels lower than in normal prostate. The most abundant N-terminal variant was DeltaN; the most abundant C-terminal variant was the alpha form. The prostate tumor cell line CWR22Rv1 contained a single G to T substitution in exon 8 that is identical to a dominant-negative DNA binding inactivation mutation occurring in patients with a congenital TP63 deficiency syndrome. One patient tumor contained a somatic mutation in exon 11.


CONCLUSIONS
The pattern of TP63 mRNA expression in normal prostate tissue is retained in reduced amounts in prostate cancer, and a potentially functional TP63 mutation was identified in one prostate tumor. Thus, if TP63 is a prostate cancer gene it likely functions as a tumor suppressor. Further study of the role of TP63 isoforms in regulating stem cell functions of normal and neoplastic prostate epithelial cells is needed. Prostate 69:559-569, 2009. (c) 2009 Wiley-Liss, Inc.
Parsons
J Kellogg
JK
Division of Urology, University of California, San Diego Medical Center, San Diego, California, USA.
Saria
Elizabeth A
EA
Nakayama
Masashi
M
Vessella
Robert L
RL
Sawyers
Charles L
CL
Isaacs
William B
WB
Faith
Dennis A
DA
Bova
G Steven
GS
Samathanam
Christina A
CA
Mitchell
Rebecca
R
De Marzo
Angelo M
AM
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D020033:Protein Isoforms; D012333:RNA, Messenger; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins