PTTG, PBF AND p53 IN HEAD AND NECK CANCER (360G-Wellcome-096537_Z_11_Z)

There has been a steady increase in the incidence of human papilloma virus (HPV) related oropharyngeal cancer in many Western countries, with a doubling of incidence over the last 10 years. HPV-oropharyngeal cancer occurs in younger patients than HPV negative disease, and is less commonly related to smoking. Unlike HPV-negative disease, the biology of HPV-positive oropharyngeal cancer is characterised by p53 degradation, retinoblastoma RB pathway inactivation, and p16 upregulation. Multiple studies have now reportedthat the proto-oncogene PTTG is over-expressed in head and neck cancer, with PTTG over-expression generally predicting higher pathological stage, more extensive lymph node metastasis and reduced survival. Together with its binding partner PBF, PTTG interacts with p53 and alters its functionality. We hypothesise therefore that the interacting proteins PTTG and PBF, which are over-expressed in head and neck cancer and bind p53, are critical to the aetiology of HNC. Our key goals therefore will be to determine the relationship between PBF, PTTG and p53 expression in human oropharyngeal tumours; to assess how p53 might regulate PBF in vitro; to dissect the contributions of PBF and PTTG to p53 ubiquitination and half-life; to examine the down-stream functional implications of altered PBF and PTTG expression in terms of apoptosis and genetic instability; and to challenge key observations of the project in primary cells from PBF and PTTG knock-out mice.