Abstract Bladder cancer is a common and deadly disease and over 15,000 people will die of this disease in the US this year. Invasive bladder cancers, which account for 25% of newly-diagnosed bladder cancers, commonly recur as lethal metastatic disease for which few effective treatments exist. Invasive bladder cancers can be molecularly classified as either luminal or the more aggressive basal subtypes which have high expression of TP63 and share molecular features with other basal/squamous tumors. We have identified an oncogene, Ataxia-Telangiectasia Group D Complementing gene (ATDC, also known as TRIM29), which is commonly expressed in human bladder cancers and drives initiation and invasive progression of bladder tumors in transgenic mice. ATDC is known to bind p53, modulate DNA damage responses, up-regulates -catenin signaling, promotes silencing of PTEN and acts as a switch triggering tumor invasion. While ATDC is an important oncogenic driver in human bladder cancers, it is not commonly mutated or amplified and the mechanism(s) regulating its expression are unknown. We find that ATDC expression marks human invasive bladder cancers which display a basal phenotype and that the basal marker, TP63, which is also known to promote invasion, appears to regulate expression of ATDC. We therefore hypothesize that TP63 induces a basal gene expression program in bladder cancer (and likely other tumors as well), requiring upregulation of ATDC which promotes tumorigenesis and invasive progression. To better characterize the role of TP63 and ATDC in invasive basal bladder cancer, we propose the following studies: SPECIFIC AIM 1: To characterize the mechanism(s) of TP63 regulation of ATDC in vitro. SPECIFIC AIM 2: To examine the role of TP63 and ATDC in invasive progression. SPECIFIC AIM 3: To characterize the contribution of ATDC to development of basal bladder cancers in vivo. Compared to other malignancies, bladder cancer is less studied resulting in a limited understanding of the driving biology and no targeted therapeutic approaches. As a medical oncologist with a clinical and research focus on patients with bladder cancer, I believe the studies proposed here are significant because understanding ATDC and TP63’s oncogenic activity in bladder cancer may lead to improved therapeutic approaches and new prognostic biomarkers for my patients. This work is innovative because we will utilize novel transgenic model systems, human samples, 3D culture systems, and next generation sequencing technology (Bru-seq, ChIP-seq) to uncover the tumor promoting events driven by ATDC and TP63 in bladder cancer. This proposal will also support my career development as a basic/translational research with specific focus on bladder cancer, an area of unmet clinical need.