Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype

Abstract

Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by over-expressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (HR 5.0, 95% CI 1.2-21.1, p=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 over-expression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.

Role of steroid receptor and coregulator mutations in hormone-dependent cancers

“…In PCa xenograft models, larger tumors are induced upon FOXA1 overexpression, suggesting that FOXA1 amplification may have functional consequences in clinical disease (52). In PCa cells, FOXA1 overexpression increases proliferation rates under low-androgen conditions (103). This phenotype is linked to the FOXA1-dependent acquisition of new AR genomic binding sites that activate a novel, CRPC-like transcriptional profile activation and prevents transcription.…”

“…that is enriched in oncogenic signaling pathways known to promote cell growth and survival in a hormone-starved environment (103). FOXA1 amplification and copy number gain are seen in 20% of primary BCa (Table 1 and refs.…”

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

“…Amplification and overexpression of FOXA1 have been detected in primary tumors but is more common in metastatic CRPC, highlighting its role in persistent AR signaling in the castrate state (Jain et al 2011, Grasso et al 2012, Cancer Genome Atlas Research 2015, Robinson et al 2015, Kumar et al 2016. Overexpression of FOXA1 has been associated with poor outcome and AR expression (Jain et al 2011, Sahu et al 2011, Gerhardt et al 2012, Robinson et al 2014. Mechanistically, high levels of FOXA1 in tumor cells may enhance AR:chromatin interactions when androgen levels are low and also enable binding of AR to non-canonical sites, both of which can drive a CRPC gene expression program , Robinson et al 2014.…”

“…Overexpression of FOXA1 has been associated with poor outcome and AR expression (Jain et al 2011, Sahu et al 2011, Gerhardt et al 2012, Robinson et al 2014. Mechanistically, high levels of FOXA1 in tumor cells may enhance AR:chromatin interactions when androgen levels are low and also enable binding of AR to non-canonical sites, both of which can drive a CRPC gene expression program , Robinson et al 2014. Interestingly, the converse also appears to be true: a number of studies have found that loss of FOXA1 can enable androgen-independent AR chromatin binding at non-canonical sites throughout the genome, and this cistromic reprogramming has been associated with enhanced AR signaling in CRPC (Sahu et al 2011, Jin et al 2014.…”

Coregulation of srGAP1 by Wnt and Androgen Receptor Signaling: A New Target for Treatment of CRPC

“…β-Catenin can also interact with FOXO transcriptional factors in response to oxidative stress to promote cells exit from the cell cycle and entry into cell quiescence [72]. FOXA1 was shown to be overexpressed in advanced prostate cancer and metastases, and over expression of FOXA1 led to enrichment of the Wnt signaling pathway [73]. Heterogeneous nuclear ribonucleoprotein K (HnRNP K) was also found to be overexpressed in prostate cancer tissues and overexpression of HnRNP K positively associated with high Gleason score and poor prognosis [74,75].…”