Androgen blockade therapy has become the mainstay for advanced prostate cancer. However, prolonged androgen blockade leads to outgrowth of androgen independent (AI) cells and the development of castration resistant prostate cancer (CRPC). The transition to androgen independence can occur through several adaptive mechanisms and usually results in the acquisition of a more aggressive phenotype, compared to their androgen sensitive progenitors. Recently, the role of MicroRNAs (miRNAs) has been demonstrated in regulation of gene expression for cancer progression, metastasis, and resistance to therapeutic strategies. However, the role of miRNAs in progression of androgen sensitive prostate cancer to CRPC has not been clearly defined. To study this transition, we subjected androgen sensitive (AS) LNCaP prostate cancer cells to androgen deprivation and androgen receptor antagonist bicalutamide (CDX) therapy until a subset of cells (CDXR) survived. Genome-wide expression profiling of miRNAs identified a subset of miRNAs that are significantly deregulated in these cells. The miR-17-92 cluster is one of the groups of miRNAs that becomes down regulated as the cancer cells progresses towards androgen blockade therapy (ADT) resistance. More than a 4 to 24-fold down regulation of these miRNAs were noted in CDXR compared to AS LNCaP cells. We monitored the expression status of the miR-17-92 cluster in patient tumor tissues, which showed down regulation of these miRNAs in 64-82% of the tissues tested. Target prediction database searches identified FGD4/Frabin, a novel RhoGEF as one of the targets of this cluster. Previous studies have shown Frabin to be involved in filopodia formation and cell migration through interaction with CDC42. Beyond this, little is known about Frabin function in cancer or whether it is involved in the development of CRPC. Western blot analysis of treated cell lysates confirmed increased expression of Frabin in AI and CDXR LNCaP cells. Analysis in tissue microarray (267 cores) showed a significant up regulation of Frabin in advanced prostate cancer tissues including AI specimens. More than 90% of the AI tissues and 88% of tissues with 8-10 Gleason scores showed a median staining intensity between 2-3-fold higher compared to BPH tissues. Ectopic expression of mir-17-92 clusters in AI PC3 cells down regulated Frabin expression and improved sensitivity of these cells to docetaxel (DTX) treatments.

Our results show a novel involvement of a miRNA cluster/mRNA axis in development of AI and aggressive prostate cancer. This study also provides important insight into the molecular mechanism of development of CRPC and identifies potential biomarkers and therapeutic targets for management of advanced prostate cancer.

Citation Format: Richard James Ottman, Jenna Levy, Ratna Chakrabarti. Association of miR-17-92 cluster and its target, Frabin, with development of aggressive prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5221. doi:10.1158/1538-7445.AM2014-5221