Upper aerodigestive tract (UADT)
cancers of the oral cavity and esophagus are a significant global health burden, and there is an urgent need to develop relevant animal models to identify chemopreventive and therapeutic strategies to combat these diseases. Antizyme (AZ) is a multifunctional negative regulator of cellular
polyamine levels, and here, we evaluate the susceptibility of
keratin 5 (K5)-AZ transgenic mice to
tumor models that combine chemical
carcinogenesis with dietary and genetic risk factors known to influence human susceptibility to UADT
cancer and promote UADT
carcinogenesis in mice. First, p53(+/-) and K5-AZ/p53(+/-) (AZ/p53(+/-)) mice were placed on a
zinc-deficient (ZD) or
zinc-sufficient (ZS) diet and chronically exposed to 4-nitroquinoline 1-oxide. Tongue
tumor incidence, multiplicity and size were substantially reduced in both ZD and ZS AZ/p53(+/-) mice compared with p53(+/-). AZ expression also reduced progression to
carcinoma in situ or invasive
carcinoma and decreased expression of the
squamous cell carcinoma biomarkers K14,
cyclooxygenase-2 and
metallothionein. Next, AZ-expressing p53(+/-) and p53 null mice were placed on the ZD diet and treated with a single dose of
N-nitrosomethylbenzylamine. Regardless of p53 status, forestomach (FST)
tumor incidence, multiplicity and size were greatly reduced with AZ expression, which was also associated with a significant decrease in FST epithelial thickness along with reduced proliferation marker K6 and increased
differentiation marker loricrin. These studies demonstrate the powerful
tumor suppressive effects of targeted AZ expression in two distinct and unique mouse models and validate the
polyamine metabolic pathway as a target for
chemoprevention of UADT
cancers.