title: FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.
abstract: Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer.
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Josefine
authors.initials: J
authors.lastname: Gerhardt
authors.forename: Matteo
authors.initials: M
authors.lastname: Montani
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Marc
authors.initials: M
authors.lastname: Beer
authors.forename: Fabian
authors.initials: F
authors.lastname: Huber
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermanns
authors.forename: Michael
authors.initials: M
authors.lastname: Müntener
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D018450:Disease Progression; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology; D055785:Gene Knockdown Techniques; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D051541:Hepatocyte Nuclear Factor 3-alpha; D034741:RNA, Small Interfering