1. Redox signalling to nuclear regulatory proteins by reactive oxygen species contributes to oestrogen-induced growth of breast cancer cells
- Author
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R B Penney, Victor Okoh, Changwon Yoo, Robert M. Jackson, Deodutta Roy, N A Garba, Jayanta Kumar Das, Quentin Felty, Alok Deoraj, Kamaleshwar P. Singh, and Shubhashish Sarkar
- Subjects
Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Breast Neoplasms ,Biology ,medicine.disease_cause ,redox regulation ,Breast cancer ,breast cancer ,Internal medicine ,Proliferating Cell Nuclear Antigen ,medicine ,Humans ,Nuclear protein ,skin and connective tissue diseases ,Cell Proliferation ,reactive oxygen species ,NRF-1 ,Estradiol ,Full Paper ,Nuclear Respiratory Factor 1 ,Growth factor ,Cell Cycle ,Cancer ,Estrogens ,p27 ,medicine.disease ,Cell Cycle Gene ,Hedgehog signaling pathway ,Cell biology ,Up-Regulation ,Genes, cdc ,Endocrinology ,Oncology ,MCF-7 Cells ,Female ,Signal transduction ,oestrogen ,Oxidation-Reduction ,Proto-Oncogene Proteins c-akt ,Oxidative stress ,Signal Transduction - Abstract
Historically, a majority of breast cancer research has focused on exploring conventional oestrogen receptor (ER) and growth factor pathways with limited investigations on alternative mechanisms of oestrogen action. Redox signalling as an alternative mechanism of oestrogen-dependent breast tumor growth is rapidly emerging with the promise of therapeutic potential. Physiologically achievable concentrations of oestrogen increase reactive oxygen species (ROS) formation in breast cancer cells (Felty et al, 2005a; Parkash et al, 2006). An increasing body of evidence supports the postulate that oxidative stress generated from exposure to oestrogen, either directly or by influencing the ER, may be an important driver in the development and evolution of human breast cancer (Okoh et al, 2011; Penny and Roy, 2013). The role of ROS in breast cancer is not new; however, a gap in knowledge currently exists with regard to how oestrogen-induced ROS signals nuclear regulatory proteins by way of redox-sensitive proteins. It is widely believed that an impaired redox signalling pathway leads to the dysregulated phosphorylation and/or dephosphorylation of proteins involved in the activation or deactivation of nuclear regulatory proteins (Okoh et al, 2011; Penny and Roy, 2013). We have previously shown that 17β-estradiol (E2)-induced DNA synthesis in MCF-7 breast cancer cells depends on mitochondrial oxidant signalling to AP-1, CREB, and NRF-1 (Felty et al, 2005a; Parkash et al, 2006). This study aims to extend our previous efforts in understanding how an increase in ROS from E2 exposure transduces a signal to nuclear regulatory proteins as well as to identify the key downstream nuclear proteins responsible for the growth of breast cancer cells. We demonstrate for the first time a molecular mechanism of E2-induced activation of NRF-1 leading to the upregulation of cell cycle genes; in addition, the impairment of p27 activity through the ROS-inducible PI3K→PDK1/2→AKT signal-transduction pathway may be necessary for E2-mediated growth of MCF-7 breast cancer cells.
- Published
- 2014