Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene.
NEU (ERBB2) and other members of the epidermal growth factor receptor (EGFR) family have been implicated in human prostate cancer (CAP) development and progression to an androgen-independent state, but the extent of involvement and precise role of this signaling pathway remain unclear. To begin addressing such open questions in an animal model, we have developed a transgenic line in which an oncogenic Neu cDNA (Neu*) driven by the probasin gene promoter is overexpressed in the mouse prostate and causes development of prostatic intraepithelial neoplasia (PIN) that progresses to invasive carcinoma. Expression profiling using microarrays, which was selectively validated and extended by immunophenotyping of Neu*-induced PIN and CAP, led to the identification of some novel biomarkers and also revealed increased expression of Egfr, Erbb3 and phosphorylated androgen receptor. In view of this information from our mouse model, which can be used to analyze further the role of Erbb signaling in prostatic tumorigenesis, we examined human prostate cancer tissue arrays by immunohistochemistry. Based on statistical analyses of the results, we propose the testable hypothesis that ERBB3, shown to be expressed in 86% of the human CAP cases that we examined, is the pivotal element of the Erbb pathway promoting tumorigenesis by heterodimerization with NEU or EGFR, while a NEU/EGFR dimer does not appear to play a significant role in CAP.
Li
Zhe
Z
Department of Genetics and Development, Genome Center and Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Szabolcs
Matthias
M
Terwilliger
Joseph D
JD
Efstratiadis
Argiris
A
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D066246:ErbB Receptors / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000235:genetics; D013997:Time Factors; D019076:Transgenes
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3