K-ras and Wnt Signaling Synergize to Accelerate Prostate Tumorigenesis in the Mouse

Abstract

Aberrant Ras and Wnt signaling are emerging as key events in the multistep nature of prostate tumorigenesis and progression. Here, we report the generation of a compound model of prostate cancer to define the synergism of activated K-ras (K-ras +/V12 ) and dominant stabilized B-catenin (Catnb +/lox(ex3) ) in the murine prostate. Recombination of floxed alleles and subsequent expression of oncogenic transgenes was mediated by Cre recombinase expression governed by the composite Probasin (PB) promoter (termed PBCre). Concomitant with elevated mitogen-activated protein kinase (MAPK) signaling, PBCre + K-ras +/V12 mice developed AH at 100 days (100% incidence) and low-grade prostate intraepithelial neoplasia and adenocarcinoma (60% and 7% incidence) by 500 days. PBCre + Catnb +/lox(ex3) mice showed reduced longevity (average 428 days) and were predisposed to PIN-like keratinized squamous metaplasia at 100 days (100% incidence) and adenocarcinoma (100% incidence) at end-point. These lesions displayed elevated Wnt signaling and basal levels of MAPK signaling. Synchronous activation of K-ras and B-catenin significantly reduced survival (average 189 days), reflecting accelerated tumorigenesis and the development of invasive carcinoma that displayed activated Wnt and MAPK signaling. Notably, expression of the basal cell marker p63 negatively correlated with tumor grade, resembling human prostate adenocarcinoma. Taken together, our data show that combinatorial oncogenic mutations of K-ras and b-catenin drive rapid progression of prostate tumorigenesis to invasive carcinoma, characterized by the synergistic elevation of androgen receptor, cyclooxygenase-2, and c-Myc. [Cancer Res 2009;69(1):94-101]

The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis

“…Moreover, STI-571 (Glivec), a tyrosine kinase inhibitor, downregulates the b-catenin-signaling activity and suppresses cell proliferation (46). Finally, additional studies showed that RAS pathway activation can strongly cooperate with Wnt signaling to drive development of several type of carcinoma in vivo (47,48), and that PI3K/AKT pathway can regulate Wnt signaling in various cancers (49). Our study emphasizes the potential cooperative link between Wnt pathway and RAS/MAPK and PI3K/AKT signaling pathways in NF1-associated tumorigenesis.…”

Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target

“…In addition, many studies have reported abnormal expression and mutation of b-catenin in PCa and in other solid cancers (Yardy & Brewster 2005). Synchronous activation of K-ras and b-catenin significantly reduced survival in a mouse model, associated with accelerated tumorigenesis and the development of invasive carcinoma (Pearson et al 2009). In addition, Wnt/b-catenin activation promoted PCa progression in another mouse model (Yu et al 2010), and the small molecule inhibitor of Wnt/b-catenin signaling, PKF118-310, has recently been shown to inhibit the proliferation of PCa cells (Lu et al 2009).…”

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

“…In mouse models with the SV40 large T-antigen, which inactivates p53 and Rb [126], or in mice expressing mutated K-ras and form invasive carcinoma [127], or in mice with loss of PTEN expression [128], β-catenin overexpression can promote highly invasive prostate cancer and squamous metaplasia, even in the absence of androgens. These findings provided strong evidence for a critical role of the Wnt/β-catenin signaling in prostate cancer development and progression.…”