Implications Of Inhibition Of Steroid Receptor Co-Activator-1 In Human Prostate Cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Prostate cancer (PCa) is still the most commonly diagnosed cancer and 2nd leading cause of death in the USA and the 3rd leading cause of death behind lung and colorectal cancers in Europe, respectively. Depending on the stage of the tumor different therapy options exist. Initially, those therapies show success and lead to tumor regression but eventually castration-resistant PCa (CRPC) develops. Androgen receptor (AR) is still active in CRPC through various mechanisms. One possibility of targeting the AR axis is inhibition of its co-regulators such as SRC-1, needed for efficient transcription of AR downstream genes. SRC-1, a member of the p160 coactivator family, is known to promote the transcriptional activity of steroid receptors like the AR as well as that of other non-steroidal transcription factors. Due to the fact that SRC-1 staining is increased in metastatic tissue of patients samples compared to clinically localized PCa our goal is to investigate the specific role of SRC-1 in PCa progression and metastatogenesis. Moreover, the question whether SRC-1 could be a target for a novel therapeutic approach will be addressed. Methods: Knock-down cell lines were generated using lentiviral-based RNAi technology. Western Blotting and qRT-PCR analysis were performed to verify knock-down efficiency. The proliferation of the different cell lines was addressed by 3H thymidine incorporation assays. Scratch (wound healing) and Boyden chamber assays were used to investigate the migratory and invasive behavior of the cell lines. Results: Immortalized benign and malignant prostate cell lines were screened for SRC-1 expression on mRNA and protein level, revealing that SRC-1 is expressed in all tested cell lines. Furthermore, knock down of SRC-1 in LNCaP and MDA PCa 2b (AR+) led to a markedly reduced AR transcriptional activity, which was verified by a reduced transcription of a downstream target gene prostate specific antigen. Whereas SRC-1 knockdown in MDA PCa 2b and PC3 cells did not show any effect on proliferation, depletion of SRC-1 negatively influenced cell proliferation of LNCaP cells. Moreover, we investigated the role of SRC-1 in the migratory and invasive behavior. While depletion of SRC-1 in PC3 and MDA PCa 2b cells significantly diminished migration, it had no effect on invasiveness. Conclusion: Together these findings demonstrate that SRC-1 is not only an important regulator of AR transcriptional activity but also affects other signaling pathways. Furthermore, SRC-1 seems to play a crucial role in migration but not in invasion and proliferation, depending on the cell lines used. Thus, SRC-1 may be a possible therapeutic target in metastatic prostate cancer, although its specific role has to be further investigated. Citation Format: Birgit Luef, Florian Handle, Frederic R. Santer, Zoran Culig. Implications of inhibition of steroid receptor co-activator-1 in human 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 618. doi:10.1158/1538-7445.AM2014-618