Negative Feedback Loop Between Serum Response Factor And Androgen Receptor In Castrate-Resistant Prostate Cancer

Despite initial response to androgen ablation, patients with advanced disease relapse to develop castrate-resistant prostate cancer (CRPC) which is difficult to treat. We previously identified Serum Response Factor (SRF) as an important transcription factor in an in vitro model of CRPC. Since CRPC is associated with androgen receptor (AR) hypersensitivity and previous studies linked SRF with AR, we investigated the relationship between SRF and AR. DHT stimulation increased SRF transcriptional activity in both parental LNCaP cells and their castration-resistant Abl subline. To investigate AR involvement in this process, AR expression was down-regulated using siRNA, resulting in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in the AR-negative PC346 DCC cells. However, when AR was over-expressed, SRF induction post-DHT was restored. To explore whether this was reciprocal, SRF was down-regulated by siRNA and AR transcriptional activity and protein expression were assessed. These experiments showed AR increased activity and expression following SRF knock-down, suggesting a negative feedback loop, which was confirmed by immunohistochemistry (IHC) in CRPC bone metastases (n=42), showing a negative association between SRF and AR positivity. This negative feedback was also supported by a computational model based on our experimental data. We next assessed cell proliferation following SRF inhibition and demonstrated that SRF inhibition by siRNA or CCG-1423 was as effective as AR inhibition in decreasing cell proliferation. Moreover concomitant inhibition of AR and SRF showed a synergistic effect. To confirm SRF relevance in clinical samples, we performed IHC staining for SRF on 94 primary tumours and 21 castration-resistant patients who received a transurethral resection of the prostate. This analysis showed that SRF nuclear staining was associated with castration-resistance with 95% of castration-resistant patients showing positive SRF staining versus only 50% of primary tumours. In addition SRF expression in bone metastases in a cohort of 38 patients who died of CRPC, was an independent predictor of survival from (a) prostate cancer diagnosis and (b) diagnosis with CRPC. Overall our data highlight the importance of SRF in CRPC and support SRF as a promising therapeutic target alone or in combination with current treatments. Citation Format: Maria Prencipe, Gillian O9Hurley, Amanda O9Neill, Dara Lundon, Lan K. Nguyen, Susie Boyce, Colm Morrissey, Helmut Klocker, Elaine W. Kay, William Gallagher, William Watson. Negative feedback loop between serum response factor and androgen receptor in castrate-resistant 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 4599. doi:10.1158/1538-7445.AM2014-4599