PO-446 Targeting co-regulators of hormone-receptors as a novel therapeutic approach for prostate and breast cancer

Abstract

IntroductionCurrent treatments for prostate cancer mainly target the Androgen Receptor (AR), however despite an initial response these treatments fail. Among the multiple mechanisms of resistance, aberrations in AR co-factors and co-regulators represent a promising therapeutic approach since co-factors and co-regulators are not susceptible to AR resistance mechanisms. Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) which lacks oestrogen receptor, progesterone receptor, and HER2 amplification. Due to the fact that a proportion of TNBC express AR and that AR expression has been associated with poor prognosis, targeting AR in TNBC is attracting increasing interest. We previously identified Serum Response Factor (SRF) as an important transcription factor in an in vitro model of castrate-resistant prostate cancer (CRPC). We showed SRF association with CRPC and survival using TMAs of CRPC tissues. A cross-talk between AR and SRF in vitro and in clinical samples was also demonstrated. Using the SRF inhibitor CCG1423, we showed that combination of CCG1423 and Enzalutamide, a new-generation AR-targeting agent, is significantly more effective than monotherapies. The aim of this study was to extend our discoveries from prostate to breast cancer.Material and methodsThree TNBC cell lines with different expression levels of SRF and AR were selected to investigate the effect of SRF inhibition on cell viability and migration. CCG1423 was used to inhibit SRF. Cell viability was assessed by MTT assay. Scratch assays were used to analyse cell migration. Immunohistochemistry (IHC) was used to assess SRF expression in 3 BC TMAs: TMA1 (n=144) and TMA2 (n=512) with different subtypes of BC and TMA3 with 138 TNBC patients.Results and discussionsMTT assays showed response to CCG1423 in the two cell lines positive for SRF (MDA-MB-231 and HS578t) with IC50 values of 20 uM, while MDA-MB-453 (SRF negative) did not respond (IC50 >80 uM). Scratch assays showed a slower gap closure in the cells treated with CCG1423 compared to controls for the SRF positive cell lines, while there was no difference in the MDA-MB-453. IHC staining for SRF for the 3 TMAs is currently being performed.ConclusionOur preliminary data suggest that SRF inhibition is effective in reducing cell viability and migration in BC cell lines. Due to SRF cross-talk with AR, its inhibition in combination with current anti-androgens represents a promising therapeutic approach not only for CRPC but also for TNBC.