Smoking, p53 Mutation, and Lung Cancer

Abstract

This issue marks the 50th Anniversary of the release of the U.S. Surgeon General’s Report on Smoking and Health. Perhaps no other singular event has done more to highlight the effects of smoking on the development of cancer. Tobacco exposure is the leading cause of cancers involving the oral cavity, conductive airways and the lung. Owing to the many carcinogens in tobacco smoke, smoking-related malignancies have a high genome-wide burden of mutations, including in the gene encoding for p53. The p53 protein is the most frequently mutated tumor suppressor in cancer, responsible for a range of critical cellular functions that are compromised by the presence of a mutation. Herein we review the epidemiologic connection between tobacco exposure and cancer, the molecular basis of p53 mutation in lung cancer, and the normal molecular and cellular roles of p53 that are abrogated during lung tumor development and progression as defined by in vitro and in vivo studies. We also consider the therapeutic potential of targeting mutant p53 in a clinical setting based upon the cellular role of mutant p53 and data from genetic murine models.

Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

“…These augment proliferation and inhibit cell differentiation (16). Suppressor gene alterations: neuroendocrine carcinoma and NSCLC can have missense mutation in p53 (17p12-13), which inactivates tumor suppression (17). In SCLC, mutation and deletion in retinoblastoma 1 (RB1) (13q14) can be observed, which produces loss of control of the G1 phase of the cell cycle and the arrest of the cell cycle (18).…”

Glucocorticoid receptors in lung cancer: new perspectives

“…Mice from the A/J strain are highly susceptible to chemically induced lung tumours but such induced tumours do not generally display mutations in p53 (Wang et al 2003), one of the most frequently mutated genes in lung cancer (Gibbons et al 2014). In a BP-induced model of lung cancer in mice harbouring mutations in p53 and/or Ink4a/Arf (Cdkn2a), the ability of budesonide to limit tumour growth is significantly affected, suggesting that these two genes are important in budesonidemediated chemo-preventative effects (Wang et al 2003).…”

“…This study again highlights the importance of p53 in playing a role in the mediation of the anti-proliferative effects of Gcs. This is interesting as many lung tumours harbour p53 mutations (46% in lung adenocarcinoma and 81% in squamous cell carcinoma) and most clinical studies suggest that lung cancers with p53 mutations carry a worse prognosis and are more resistant to treatment (Gibbons et al 2014).…”

Expression of mutant p53 in oral squamous cell carcinoma is correlated with the effectiveness of intra-arterial chemotherapy

“…Various studies have demonstrated that mutation of the p53 gene has a significant role in tumor development (12)(13)(14)(15)(16)(17). When DNA is damaged by physical and/or chemical factors, p53 gene transcription is increased and wild-type p53 protein is concentrated, which results in arrest of the cell cycle at G1/S phase and apoptosis of cells with cancerous characteristics (18).…”