The Role of Transcription Factors in Driving Aggressive Phenotype in Non-Invasive Bladder Cancer

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Project summary Bladder cancer is most commonly diagnosed at an early stage, where it has not invaded into the bladder wall or has done so minimally. Treatment is resection of the tumor, by fragmenting it and removing through the urethra. Patients with early stage bladder cancer uncommonly die from the disease, though the tumor usually recurs, requiring additional resections. A subset of patients progresses to advanced stage disease, with is often lethal. Treatment of early stage bladder cancer is aimed at reducing recurrence and progression to advanced stage disease. However, it is difficult to predict which patients will recur and progress. Available treatments are also largely limited to transurethral resection and instillation of attenuated bacillus (a bacterium) into the bladder, which induces inflammation. This latter treatment reduces risk of recurrence and likely progression, but is painful and can cause profound difficulties with urination and occasional sepsis. Better methods are needed to prognosticate and treat this disease. In ongoing experiments, we have found that progression is more common in early stage bladder cancers that express high levels of Spalt-like-4 (SALL4). This gene is typically not expressed in adult tissues, but is rather expressed in developing embryos. It is a transcription factor, which binds DNA and alters expression of other genes. Prior studies have shown SALL4 is expressed in many cancer types, and expression drives tumor growth and proliferation, as well as aggressive behavior in other tumor types. Our experiments have likewise shown SALL4 may drive cellular proliferation in bladder cancer, a feature associated with increased risk of recurrence and progression in other studies. We also have evidence SALL4 directly activates the cell cycle, the process underlying cellular proliferation. Patients with bladder cancer would benefit from understanding SALL4 in this disease, as it could be used to predict which patients will recur and progression, and could be a target of therapy. Given these findings, We hypothesize that SALL4 drives cellular proliferation in early stage bladder cancer, thereby driving stage progression, specifically by directly activating cell cycle programs. We will address this hypothesis with these Specific Aims: (1) establish the relationship between expression of genes involved in the cell cycle, and SALL4 binding at DNA regions that regulate their expression; and (2) determine the direct effects of reducing or increasing SALL4 expression in cell lines and mouse xenograft models, specifically the effects on activity of the cell cycle, cellular proliferation, tumor growth, and invasion.