Research Description
Transcription factors regulate highly complex gene networks. This is exemplified by the p53 family of transcription factors, which contains three members, p53, p63, and p73, and a total of over 50 protein isoforms that all have the ability to bind DNA. The mammalian p53, p63, and p73 genes descended from an ancestral gene and share a common domain architecture and significant sequence identity. However, their differences in vivo are striking. While p53 is mutated in over 50% of human tumors, p63 and p73 are rarely mutated. Instead, the p63 locus is amplified in a small percentage of squamous carcinomas, and p73 is over-expressed in several tumor types. In addition, while p53 null mice have an increased frequency of spontaneous tumor formation, p63 and p73 null mice die tumor-free from developmental defects. Although p63 and p73 can engage apoptotic pathways, it is clear that they are not classic Knudson-like tumor suppressors like p53.
Over the past 25 years there have been ~81,000 publications involving the characterization and analysis of p53; however, efforts to exploit p53 in cancer therapies have not paid off to date. The Pietenpol Laboratory is looking to p63 and p73 as alternative routes to therapeutic targets as well as targeting mutant p53 gain-of-function activity and translating basic research findings to investigator-initiated clinical trials. Our competitively-funded research program was one of the first to pioneer techniques for analysis of p53-chromatin binding and identification of p53 target genes. The laboratory discovered that p63 signaling confers key epithelial properties to cells by regulating novel target genes and transcriptional programs controlling mesenchymal phenotypes. The group deciphered the functional p73 binding sites in the genome, discovered numerous mRNAs and microRNAs that are direct targets of p73 regulation, and was the first to link the mTOR signaling pathway to regulation of p73 activity.
These basic discoveries led the Lab to generate pre-clinical data for phase I and phase II trials for women with difficult-to-treat, triple negative breast cancer (TNBC). The hypotheses being tested in the trials as well as the compilation of genomic analyses of biospecimens with publically available genomic data sets led to the molecular subclassification of triple negative breast cancer (TNBC) into six subtypes. These results provide great insight to the heterogeneity of the disease and are being translated to new hypotheses for bench-based discoveries, ongoing clinical trials and alignment of patients to molecularly targeted therapy.
Most recently, the Pietenpol team discovered that p73 is required for multiciliogenesis and regulates the Foxj1-associated gene network. This seminal discovery provides a unifying mechanism for many phenotypes observed in p73 knockout mice including hydrocephalus, hippocampal dysgenesis, sterility and chronic inflammation/infection of lung, middle ear and sinus. We identified over 100 p73-target genes that regulate multi-ciliated cell (MCC) differentiation and homeostasis and that p63 and p73 are co-expressed in a subset of basal cells and that p73 ‘licenses’ these cells for MCC differentiation.
To date, Dr. Pietenpol has trained over 45 graduate students, postdocs, and clinical fellows. Her trainees hold independent faculty, staff, and leadership positions in academics and in the pharmaceutical or biotechnology industries.