Abstract 3878: Perturbations in the AR-cyclin D1 axis controls lethal tumor phenotypes in prostate cancer

Abstract

Abstract Androgen receptor (AR) signaling is critical to prostate cancer development. It has been well established that AR activation promotes lethal tumor phenotypes including proliferation, survival, invasion, and therapeutic resistance. However, mechanisms by which AR promotes these phenotypes are poorly understood. Previous reports assessing cellular proliferation revealed that the AR-cyclin D1a axis plays a significant role in controlling the response to androgen. While activated AR induces cyclin D1a through mTOR mediated mechanisms, accumulated cyclin D1a serves a negative feedback control function, through the ability of the cyclin to bind and suppress further AR signaling. Importantly, this process is frequently abrogated in human prostate cancer through an alternative splicing event that results in production of cyclin D1b. Cyclin D1b is deficient in its ability to regulate AR, and has been shown in other model systems to harbor significant oncogenic activity. Importantly, we have demonstrated that nearly 1/3 of a large cohort of primary prostate cancer tumors exclusively express cyclin D1b. Thus, it is imperative to determine the molecular and cellular consequence of the alternative splicing event in prostate cancer. Endogenous D-cyclins were eliminated using hormone ablation; subsequent viral-mediated reintroduction of cyclins D1a or D1b allowed for unbiased comparison of cyclin function in the presence and absence of androgen. Gene expression profiling confirmed that D1b is unable to manage AR activity. Concordantly, alteration of androgen-sensitive genes was observed, in particular those associated with migration and invasion. In vitro manipulation of the D1 splicing event confirmed these results. Subsequent modeling of cyclin D1b function revealed that cyclin D1b confers a specific anchorage independence and migration phenotype to AR-positive prostate cancer cells. Thus, these data provide the first evidence that perturbation in the AR-cyclin D1 axis controls lethal tumor phenotypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3878.