title: 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 overexpressing 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 (hazard ratio (HR) 5.0, 95% confidence interval (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 overexpression 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.
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: J L L
authors.initials: JL
authors.lastname: Robinson
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: T E
authors.initials: TE
authors.lastname: Hickey
authors.affiliation: Department of Histopathology, Cambridge University Hospitals NHS Foundations Trust, Cambridge, UK.
authors.forename: A Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Vowler
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: T
authors.initials: T
authors.lastname: Carroll
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Oncology, University of Cambridge, Cambridge, UK [3] Department of Urology, Cambridge University Hospitals NHS Foundations Trust, Cambridge, UK.
authors.forename: A D
authors.initials: AD
authors.lastname: Lamb
authors.affiliation: Department of Urology, Cambridge University Hospitals NHS Foundations Trust, Cambridge, UK.
authors.forename: N
authors.initials: N
authors.lastname: Papoutsoglou
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Oncology, University of Cambridge, Cambridge, UK [3] Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: D E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate Cancer Research Centre, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: W D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: 1] Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK [2] Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Carroll
mesh_terms: D000368:Aged; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: C410798:AR protein, human; D002843:Chromatin; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011944:Receptors, Androgen