Project description:Our findings suggested that tamxofen resistance induced by RB depletion depends on increased IL-6 production. To elucidate molecular mechanism, we employed whole genome microarray expression profiling as a discovery platform to identify IL-6-dependent RB inactivation signature. RB depleted MCF7 and control MCF7 were cultured with 2 ug/ml anti-IL-6 antibody or IgG, and a 35-gene signature upregulated by RB depletion in an IL-6 dependent manner was identified. This gene set was highly enriched in genes involved in mitochondrial respiration chain. These data revealed that activation of mitochondrial respiration contribute to RB-depletion induced tamoxifen resistance.
Project description:The retinoblastoma (RB) tumor suppressor is functionally inactivated in a wide range of human tumors where this inactivation promotes tumorigenesis in part by allowing uncontrolled proliferation. RB has been extensively studied, but its mechanisms of action in normal and cancer cells remain only partly understood. Here we describe a new mouse model to investigate the consequences of RB loss and its re-activation in vivo. In these mice, induction of shRNA molecules targeting RB for knock-down results in the development of phenotypes similar to RB knock-out mice, including the development of pituitary and thyroid tumors. Re-expression of RB leads to cell cycle arrest in cancer cells and repression of transcriptional programs driven by E2F activity. Thus, continuous RB loss is required for the maintenance of tumor phenotypes initiated by loss of RB, and this new mouse model will provide a new platform to investigate RB function in vivo.
