Abstract
Approximately 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastatic disease, which is almost invariably lethal. However, our understanding of pathways that drive aggressive behavior of MIBC is incomplete. Members of the FOXA subfamily of transcription factors are implicated in normal urogenital development and urologic malignancies. FOXA proteins are implicated in normal urothelial differentiation, but their role in bladder cancer is unknown. We examined FOXA expression in commonly used in vitro models of bladder cancer and in human bladder cancer specimens, and used a novel in vivo tissue recombination system to determine the functional significance of FOXA1 expression in bladder cancer. Logistic regression analysis showed decreased FOXA1 expression is associated with increasing tumor stage (p<0.001), and loss of FOXA1 is associated with high histologic grade (p<0.001). Also, we found that bladder urothelium that has undergone keratinizing squamous metaplasia, a precursor to the development of squamous cell carcinoma (SCC) exhibited loss of FOXA1 expression. Furthermore, 81% of cases of SCC of the bladder were negative for FOXA1 staining compared to only 40% of urothelial cell carcinomas. In addition, we showed that a subpopulation of FOXA1 negative urothelial tumor cells are highly proliferative. Knockdown of FOXA1 in RT4 bladder cancer cells resulted in increased expression of UPK1B, UPK2, UPK3A, and UPK3B, decreased E-cadherin expression and significantly increased cell proliferation, while overexpression of FOXA1 in T24 cells increased E-cadherin expression and significantly decreased cell growth and invasion. In vivo recombination of bladder cancer cells engineered to exhibit reduced FOXA1 expression with embryonic rat bladder mesenchyme and subsequent renal capsule engraftment resulted in enhanced tumor proliferation. These findings provide the first evidence linking loss of FOXA1 expression with histological subtypes of MIBC and urothelial cell proliferation, and suggest an important role for FOXA1 in the malignant phenotype of MIBC.
Highlights
It is estimated that in 2011 over 69,250 people in the United States will be diagnosed with carcinoma of the urinary bladder [1]
FOXA1 and FOXA2 expression is restricted to specific bladder cancer cell lines: In studies of urinary bladder development, nuclear FOXA1 expression was found to be restricted to the urothelial compartment and was maintained in adult urothelium [27]
Expression of FOXA1 was associated with the presence of UPK transcripts (Fig 1A), of which UPK2 is used as a urothelial differentiation marker. 5637 cells co-expressed low levels of FOXA1 and UPK mRNA
Summary
It is estimated that in 2011 over 69,250 people in the United States will be diagnosed with carcinoma of the urinary bladder [1]. Most patients present with non-invasive disease, but often develop recurrence, sometimes with progression to stromal invasion. Vigilant surveillance of these patients by periodic cystoscopy and urine cytology is required following tumor treatment. Clinical management for patients with Ta or Tis disease is extraordinarily expensive [1]. Clinical intervention following the diagnosis of muscle invasive bladder cancer (MIBC; tumor stage$T2) typically entails radical cystectomy. Approximately 50% of patients undergoing radical cystectomy will experience disease recurrence, usually in the form of metastatic disease. The development of metastatic disease is almost invariably lethal, and it is estimated in 2011 that over 14,990 individuals in the United States will perish from metastatic bladder cancer in the United States [1]
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