Inactivation of Apc in the Mouse Prostate Causes Prostate Carcinoma

Abstract

Alterations of the Wnt/B-catenin signaling pathway are positively associated with the development and progression of human cancer, including carcinoma of the prostate. To determine the role of activated Wnt/B-catenin signaling in mouse prostate carcinogenesis, we created a mouse prostate tumor model using probasin-Cre-mediated deletion of Apc. Prostate tumors induced by the deletion of Apc have elevated levels of B-catenin protein and are highly proliferative. Tumor formation is fully penetrant and follows a consistent pattern of progression. Hyperplasia is observed as early as 4.5 weeks of age, and adenocarcinoma is observed by 7 months. Continued tumor growth usually necessitated sacrifice between 12 and 15 months of age. Despite the high proliferation rate, we have not observed metastasis of these tumors to the lymph nodes or other organs. Surgical castration of 6-week-old mice inhibited tumor formation, and castration of mice with more advanced tumors resulted in the partial regression of specific prostate glands. However, significant areas of carcinoma remained 2 months postcastration, suggesting that tumors induced by Apc loss of function are capable of growth under conditions of androgen depletion. We conclude that the prostate-specific deletion of Apc and the increased expression of B-catenin associated with prostate carcinoma suggests a role for B-catenin in prostate cancer and offers an appropriate animal model to investigate the interaction of Wnt signaling with other genetic and epigenetic signals in prostate carcinogenesis.

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

“…Adenocarcinomas showed increased severity compared with those at 200 days and keratinized squamous metaplasia was rarely detected. Notably, these lesions resembled the MMTV-Cre + Catnb +/lox(ex3) and PBCre + Apc fl/fl models described previously (25)(26)(27). Indeed, prostate cancer progression in PBCre + Catnb +/lox(ex3) mice closely mirrors that of Apc mutant mice, consistent with Wnt signaling deregulation.…”

“…Analysis of K-ras (LG-PIN), b-catenin (adenocarcinoma), and double transgenic (invasive carcinoma) mice at end point revealed that p63 expression decreases with prostate tumor progression (7.1%, 2.9%, and 0.1%, respectively). These data mimic human prostate cancer (27), bladder tumors (36), and head and neck squamous carcinoma (37).…”

“…Mouse mammary tumor virus (MMTV)-Cre mediated dominant stabilization of h-catenin in the prostate been shown to predispose to PIN-like keratinized squamous metaplasia (25,26), whereas deletion of the h-catenin regulator APC, mediated by PBCre, results in androgen-independent prostate adenocarcinoma (27), highlighting the importance of the Wnt cascade during tumorigenesis and disease progression.…”

Molecular genetics of prostate cancer: new prospects for old challenges

“…Other commonly used models have employed conditional deletion mediated by the Pb-Cre4 transgene, which uses a modified probasin promoter (ARR 2 PB) to drive Cre expression in the prostate epithelium (Wu et al 2001), although a potential concern is that this Cre allele also drives recombination in the stroma (X Wang and MM Shen, unpubl.). The Pb-Cre4 driver has been used by many laboratories for the conditional deletion of Pten as well as other genes of interest Bruxvoort et al 2007). Another popular Cre driver is the Nkx3.1-Cre knock-in allele, which expresses Cre recombinase specifically in the prostate epithelium, but also in several other tissues during embryogenesis (Stanfel et al 2006;Lin et al 2007;Thomsen et al 2008;Zhang et al 2008).…”

“…In particular, elevated canonical Wnt signaling may play a role in the emergence of castration resistance (G Wang et al 2008), while prostate cancer in mice can result from inactivation of Apc or overexpression of a constitutively active b-catenin together with activated K-ras (Bruxvoort et al 2007;Pearson et al 2009;Yu et al 2009). In contrast, however, evidence from human tumors suggests that nuclear localization of b-catenin is inversely correlated with tumor progression (Horvath et al 2005;Whitaker et al 2008), suggesting that canonical Wnt signaling may not play a significant role in prostate cancer progression.…”