Presentation Authors: Lauren Shuman*, Vasty Osei-Amponsa, Jenna Buckwalter, Zongyu Zheng, Hironobu Yamashita, Vonn Walter, Justine Ellis, Hershey, PA, Chang Lu, New York, NY, Joshua Warrick, Lisa Shantz, Robert Feehan, Hershey, PA, Hikmat Al-Ahmadie, Cathy Mendelsohn, New York, NY, Klaus Kaestner, Philadelphia, PA, Xue-Ru Wu, New York, NY, David DeGraff, Hershey, PA
Introduction: Advanced bladder cancer exhibits a unique degree of morphologic and molecular intratumoral heterogeneity. While tumor heterogeneity in bladder cancer is associated with clinical outcome and therapeutic response, the mechanism(s) responsible for emergence of this phenotype are largely unknown. We previously identified decreased expression of the urothelial differentiation factor FOXA1 within bladder cancers exhibiting heterogeneity in the form of squamous differentiation. In addition, PTEN inactivation was recently associated with â€œsquamous-likeâ€ cancers of the bladder and other organs. These observations suggest a potentially cooperative role for FOXA1 and PTEN loss in the development of bladder cancer and/or associated tumor heterogeneity. Therefore, we initiated a study focused on identifying mechanisms underlying reduced PTEN and FOXA1 expression in bladder cancer, as well as their functional contribution to disease.
Methods: Gene expression and copy number alteration analysis was conducted using human data through The Cancer Genome Atlas Bladder project. In addition, to determine the functional consequence of reduced PTEN and FOXA1 expression in disease, we conditionally ablated Foxa1 and/or Pten in the urothelium of mice.
Results: We confirm that like decreased FOXA1 expression, decreased PTEN is common in bladder cancer. However, decreased PTEN expression is not associated with a specific morphologic characteristic or gene expression subtype. We show copy number alterations are likely a major factor determining PTEN expression, while FOXA1 expression is relatively independent of copy number. Combined inactivation of Foxa1 and Pten in mice results in the development of bladder cancer with squamous features. Additionally, exposure of these mice to a bladder-specific carcinogen results in rapid development of advanced disease with extensive squamous differentiation.
Conclusions: In summary, through the integration of clinical and animal studies, we identify genetic events which contribute to reduced PTEN and FOXA1 expression, and provide evidence of their contribution to human disease.
Source of Funding: Supported by K99CA172122 (DJD), R00CA172122 (DJD) and startup funding from the Departments of Pathology and Surgery at Pennsylvania State University College of Medicine (DJD).