p73: context-dependent roles in tumorigenesis
While p53 is the most mutated gene in cancers, its homologue p73 is often overexpressed in many cancers, without being mutated. These observations suggest that p73 may have diverse roles in regulating tumorigenesis. While absence of TAp73 (full-length form) promotes tumor formation in mice – albeit weakly, highlighting a role in tumor suppression, its role in supporting tumor growth had been controversial.
Work from our laboratory over the years has focused on understanding this tumor promoting property, and we have previously shown that TAp73 is capable of driving cellular proliferation in specific contexts, through the regulation of AP-1 target genes. Recently, we have demonstrated that TAp73 is capable of inducing the expression of angiogeneic genes, especially in hypoxic conditions that are prevalent in tumors. Thus, TAp73 appears to be utilizing multiple mechanisms to promote cancer cell growth, implying that these tumor promoting pathways may be targetable for improving therapeutic response. We have therefore embarked on identifying key molecular determinants of the TAp73 pathway through high-throughput whole-genome siRNA screens and proteomics approaches, with the eventual goal of inhibiting them to reduce angiogenesis and proliferation of cancer cells. In addition, given the diametrically opposite roles of TAp73 in both promoting and suppressing tumor formation, we are now poised to address the question on how a transcription factor like TAp73 is able to regulate these seemingly opposite cell fate outcomes. We are using animal models to study the spatial and temporal role of TAp73 within the tumor exclusively, as well as in the stromal compartments.