Conditional Deletion of Rb Causes Early Stage Prostate Cancer

Abstract

Prostate cancer remains the second leading cause of cancer-related death for men in the United States. Mutations in tumor suppressor genes including retinoblastoma (Rb), p53, and PTEN have been linked to the development of prostate cancer in man and mouse models, and loss of heterozygosity of the Rb locus has been observed in up to 60% of clinical cases. In this study we demonstrate that conditional somatic deletion of even a single Rb allele in the epithelial cells of the mouse prostate causes focal hyperplasia, thereby establishing a causal relationship between Rb loss and development of early stage prostate cancer. As a consequence of Rb ablation we observed increased expression of E2F target genes and a concomitant increase in proliferation in the epithelial compartment. However, by 52 weeks of age these lesions had not become malignant and represent an early stage of the disease. Nevertheless, the multifocal nature of the phenotype in the mice closely resembled multifocality of clinical disease. Taken together, our data demonstrated that loss of pRB-mediated cell cycle control directly caused the initiation of proliferative prostate disease but was insufficient to cause malignancy. Establishment of this early initiation model will aid efforts to thoroughly characterize early prostate disease as well as the elucidation of molecular mechanisms that cooperate with Rb loss to facilitate progression and metastasis.

p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells

“…Loss of Rb results in unrestrained proliferation and p53-mediated apoptosis via activation of E2F1 and its responsive genes (38,39). Regarding prostate cancer, loss of Rb function due to loss of heterozygosity of Rb locus (13q14) has been observed in 60% clinical cases (40); thus, it became pertinent to conduct our mechanistic studies in cell lines differing in the status of Rb as well as p53. DU145 cells are androgen insensitive and harbor both p53 and Rb mutations.…”

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

“…In Western blotting, GAPDH was used as a loading control. (Maddison et al, 2004). pRB plays a critical role in cell cycle progression by binding and inhibiting E2Fs, and hence preventing S-phase entry, until it is phosphorylated by CDKs.…”

Pocket proteins and cell cycle control

“…A subset of the apoptotic responses resulted from defective placental function and the ensuing hypoxia (Wu et al, 2003), but the proliferation and differentiation defects were generally cell autonomous. Additional proliferation and differentiation defects have been observed postnatally in tissue-specific Rb knockouts in the pituitary, lung, cerebellum, retina, prostate, and skin (Vooijs et al, 1998;Marino et al, 2003;Chen et al, 2004;MacPherson et al, 2004;Maddison et al, 2004;Ruiz et al, 2004;Wikenheiser-Brokamp, 2004;Zhang et al, 2004a). p107 and p130 are needed to control proliferation and differentiation in a more limited spectrum of tissues, including cartilage, epidermis, and brain Ruiz et al, 2003;Vanderluit et al, 2004).…”