Novel roles of the RB-pathway in human cancers: Modifying disease progression and establishing new therapeutic opportunities
Deregulation of the retinoblastoma (RB) tumor suppressor pathway, a critical negative regulator of cell cycle control and proliferation, is observed in a wide variety of human cancers. Emerging studies have implicated RB protein function not only in cell proliferation but also in other essential cellular processes such as differentiation and chromosomal instability, among others. However, how deregulation of the RB-pathway directly impacts certain critical aspects of tumorigenesis and disease progression still remains an enigma. Herein, using breast cancer models, we have identified novel implications of RB-pathway deregulation that contribute to disease progression. RB loss in cooperation with epidermal growth factor 2 (ErbB2), a prominent oncogene activated in breast cancer, promotes structural and organizational changes in mammary epithelial cells correlating with an epithelial-to-mesenchymal transition gene signature, and ultimately an invasive phenotype in mammary lesions in vivo. Additionally, due to the clear importance of RB in suppressing tumorigenesis in multiple tissue types, we examined the efficacy of using a small molecule CDK4/6 inhibitor (PD-0332991) to "activate" RB function as a potential therapeutic modality in both early stage breast cancer and advanced liver cancer models. CDK4/6 inhibition was observed to be highly effective at inducing a potent cytostatic response in both model systems. Importantly, we demonstrate that the efficacy of PD-0332991 is dependent on the expression of multiple key players in cell cycle control aside from RB itself, including the other pocket proteins (p107/p130), p16 ink4a and Cyclin D1. Together these studies demonstrate the utility of RB-pathway status as both a predictor for invasive disease and a novel therapeutic target.
Rivadeneira, Dayana B, "Novel roles of the RB-pathway in human cancers: Modifying disease progression and establishing new therapeutic opportunities" (2012). ETD Collection for Thomas Jefferson University. AAI3518735.