FOXA1 Promotes Tumor Progression in Prostate Cancer and Represents a Novel Hallmark of Castrate Resistant Prostate Cancer
Matteo Montani, Josefine Gerhardt, Glen Kristiansen. University of Bern, Bern, Switzerland; University Hospital of Zurich, Zurich, Switzerland; University Hospital Bonn, Bonn, Germany
Background: Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. Therefore, we investigated FOXA1 expression in a large cohort of prostate cancer patients of different stages in order to correlate it to clinical parameters, PSA relapse free survival and hormone receptor expression.
Design: We investigated a cohort of 529 Patients who underwent radical prostatectomy, transurethral resection or resection of organ metastasis of prostate cancer or benign hyperplasia (primary carcinomas (n=207), castrate-resistant prostate cancer (n=27), lymph node and distant metastases (n=39), benign prostatic hyperplasia (n=15)). A tissue microarray (TMA) was constructed. Follow-up data was obtained for the group of primary carcinomas. Immunohistochemical stainings of FOXA1, AR, ER, PR, PSA a.o. was evaluated. To determine if FOXA1 expression has an influence on prostate cancer cell proliferation, LNCaP and PC-3 cells were transfected with FOXA1 specific siRNAs and cells were counted. DNA synthesis rate was determined by measuring BrdU incorporation. FOXA1 expression during cell migration was elucidated in a transmigration assay towards fibronectin. We reanalyzed the proliferation and migration behavior of FOXA1 high and low LNCaP cells upon androgen treatment.
Results: FOXA1 was overexpressed in metastases and particularly in castration resistant cases. Interestingly, FOXA1 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 androgen and estrogen receptor expression. FOXA1 overexpression was associated with faster biochemical disease progression, which was even pronounced in cases with low AR levels. Finally, siRNA based knockdown of FOXA1 decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was only inducible by androgens in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR.
Conclusions: In conclusion, FOXA1 expression is associated with tumor progression, de-differentiation of prostate cancer and poorer prognosis as well as cellular proliferation and migration and androgen signaling. These findings suggest FOXA1 overexpression as a novel mechanism to induce castration resistance in prostate cancer.
Category: Genitourinary (including renal tumors)
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 175, Wednesday Afternoon