Liver cancer is the third leading cause of cancer deaths throughout the world. The major risk factors for development of this disease are environmental in nature. These risk factors include agents that strongly modulate tumor susceptibility such as chronic infection with hepatitis B virus or exposure to the DNA damaging hepatocarcinogen aflatoxin B1 (AFB1). Tumor development is largely driven by genetic lesions that subvert critical cellular pathways. 1 such pathway, the retinoblastoma tumor suppressor (RB) pathway is mutated in the majority of liver tumors. Although RB is mutated in most liver tumors, how RB loss specifically contributes to tumorigenesis in the liver is unknown. Furthermore, the interplay between RB-deficiency and exposure to the environmental agents that cause liver cancer, e.g. AFB1, and how this impacts tumor formation is unclear. This is a critical consideration because it is well established that RB is required for the appropriate cell cycle checkpoint response to DNA damage. In the absence of RB, cells continue to proliferate in the presence of DNA damage, inducing additional mutations and leading to genome instability, a hallmark of cancer cells. Critically, the role of RB in DNA damage checkpoints in animals and how checkpoint abrogation contributes to tumorigenesis has not been studied. We have generated mice that have hepatocyte-specific RB-deficiency. We have found that RB deficiency causes abnormal hepatocyte ploidy (total DNA content), suggesting that these cells are inherently genetically unstable. We have also found that RB loss predisposes to the induction of liver tumors following genotoxic damage. Thus, we hypothesize that RB loss enhances tumor formation in the liver following exposure to environmentally-relevant genotoxic carcinogens, such as AFB1. We propose to delineate how RB modifies the response to AFB1 in the mouse liver and probe how this contributes to tumor formation. First, we will determine how RB loss influences the acute checkpoint response of the liver to AFB1 exposure and identify features of this aberrant response (e.g. development of genome instability) that may be important for driving tumor formation. Second, we will specifically elucidate the effects of RB-loss on AFB1-induced liver tumor development in the mouse. These studies will identify critical facets of RB function in vivo and delineate specific consequences of RB loss that are germane to tumor formation following genotoxic insult. ? ? ?
|Knudsen, Erik S; Sexton, Charlene R; Mayhew, Christopher N (2006) Role of the retinoblastoma tumor suppressor in the maintenance of genome integrity. Curr Mol Med 6:749-57|
|Knudsen, Erik S; Knudsen, Karen E (2006) Retinoblastoma tumor suppressor: where cancer meets the cell cycle. Exp Biol Med (Maywood) 231:1271-81|