Abstract 4190: A mouse model of pRb2/p130 in prostate cancer

Abstract

INTRODUCTION

Prostate Cancer (PCa) is the most commonly diagnosed cancer in men and it is responsible for the second highest number of cancer-related deaths in the United States. There is an urgent need for new treatments and better experimental animal models to study PCa development, progression, and metastasis.

Prostate cancer is a heterogeneous and multifocal disease that arises from several genetic and epigenetic aberrations. Among different altered pathways, the Retinoblastoma is inactivated in more than fifty percent of PCa. Despite a plentiful literature, the activity of pRb members (pRb, pRb2/p130 and p107) is not fully elucidated.

From a previously published mouse model, we know that the inactivation of all the pRb members induces aberrant proliferation and it is sufficient for tumor initiation.

Here, we describe a novel double ko (Rb, pRb2/p130) mouse model, which offers a new opportunity to dissect prostate tumor initiation and development.

MATERIALS AND METHODS

To study the effect of pRb2/p130 inactivation on prostate tumorigenesis and progression, we knocked out pRb and/or pRb2/p130 in the prostate tissue (Probasin-CRE). The genotypes of each gene were determined by PCR. To analyze the effects of pRb2/p130 loss, we collected prostate tissues at different time points (3, 6, 9, 12 and 18 months). A portion of each prostate sample was fixed in formalin and embedded in paraffin to perform immunohistochemistry analyses and another portion was flash-frozen for molecular studies.

The histological classification of each prostate samples was made on H&E-stained sections by A.K.S., a veterinary pathologist with extensive experience in murine prostate pathology.

RESULTS

As reported in literature, pRb family disruption in the prostate epithelium induces prostatic intraepithelial neoplasia. The prostate of triple ko mice showed extensive abnormal gland architecture beginning as early as 2 months of age with a focal hyperplasia. By 3 months of age, all the triple ko mice displayed characteristic traits of murine prostatic intraepithelial neoplasia (mPIN). Double ko (pRb and pRb2/p130) mice developed hyperplasia after 6 months and focally invasive well-differentiated adenocarcinomas by 12-18 months.

CONCLUSIONS

Our preliminary findings suggest that the inactivation of pRb and pRb2/p130 leads to the development of a prostate tumor phenotype and highlight the importance of the function of pRb2/p130 in the prostatic epithelium.

This model will be useful to clarify the molecular mechanism of pRb2/p130 function and represents a new opportunity for cancer therapy.

Citation Format: Silvia Boffo, Andres J. Klein-Szanto, Flavio Rizzolio, Antonio Giordano. A mouse model of pRb2/p130 in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4190. doi:10.1158/1538-7445.AM2015-4190