Abstract A50: Cyclin D1 isoforms selectively manipulate AR signaling to promote metastatic phenotypes in early and castration-resistant prostate cancer.

Abstract

Abstract Cyclin D1 is a well-known inducer of cell cycle progression but has only recently been appreciated as a transcriptional regulator, controlling a milieu of transcriptional networks involved in both development and cancer. Intriguingly, while Cyclin D1 has only limited oncogenic activity, a variant that arises through oncogene induced alternative splicing (Cyclin D1b) has markedly enhanced oncogenic potential (as judged by in vitro and in vivo assays). Biochemical interrogation demonstrated that Cyclin D1b had little influence on cell cycle progression, indicating that oncogenic properties exerted by Cyclin D1b were likely transcriptionally regulated. Consonantly, it was shown that Cyclin D1b (but not full length Cyclin D1) is preferentially upregulated in malignant prostate cancers. Here, models were developed to determine the tumor-specific functions of Cyclin D1b, and unbiased analysis performed to assess cellular consequence. First, expression of Cyclin D1b was found to promote anchorage independent growth and enhance invasive potential in an androgen receptor (AR) dependent manner, while exerting no effect on cell cycle progression. Second, a large transcriptional network was determined to be uniquely under the control of Cyclin D1b, a subset of which are known AR target genes. Among this AR regulated gene set was the transcriptional regulator SNAI2 (SLUG), known to promote phenotypes associated with cancer progression and metastasis in various systems. Third, the molecular mechanisms underpinning Cyclin D1b function were revealed as Cyclin D1b enhanced AR occupancy at conserved AR bindings sites at SNAI2 regulatory loci, which correlated with chromatin modifications associated with active transcription. Fourth, molecular inhibition of SNAI2 levels was sufficient to inhibit D1b induced phenotypes both in vitro and in vivo. Finally, while both Cyclin D1b and SLUG are expressed in nearly 1/3 of primary prostate tumors, relative expression is increased in metastatic as well as castration resistant prostate cancer samples, indicating the Cyclin D1b/SLUG pathway is likely involved in disease progression. Together, the study to be presented defines a mechanism to explain Cyclin D1b-mediated effects in human disease, provides evidence of a direct AR driven gene that is induced exclusively during PCa progression, and identifies the Cyclin D1b/AR/SLUG axis as a major pathway associated with metastatic phenotypes. Citation Format: Michael A. Augello, Craig Burd, Ruth Bribe, Daniel Frigo, Jason Karch, Donald McDonnell, Tapio Visakorpi, Karen E. Knudsen. Cyclin D1 isoforms selectively manipulate AR signaling to promote metastatic phenotypes in early and castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr A50.