One in eight women will suffer breast cancer during their lifetime. About 70% of breast cancer depends on the presence of estrogen to grow, and is classified as Estrogen Receptor (ER) positive and estrogen dependent. ER regulates the expression of many genes, among which is Cyclin D1. Our recently research reported that EglN2, an estrogen inducible gene, positively regulates Cyclin D1 and contributes to breast tumorigenesis. The regulation of Cyclin D1 by EglN2 is largely dependent on EglN2 prolyl hydroxylase activity. However, the mechanism underlying the regulation of Cyclin D1 by EglN2 remains largely unknown. In order to identify the potential EglN2 prolyl hydroxylase substrates that mediate this process, I performed in vitro hydroxylation screening for EglN2 substrates. FOXO3a was identified as a potential EglN2 target. I plan to validate FOXO3a as a novel EglN2 substrate (Aim 1) and examine whether FOXO3a mediates the effect of EglN2 on Cyclin D1, breast cancer cell proliferation in vitro and in vivo (Aim 2). Lastly, I will systematically search for FOXO3a direct transcription targets in EglN2-mediated breast tumorigenesis (Aim 3). The proposed research will elucidate the mechanism by which EglN2 mediates breast tumorigenesis and the important role of FOXO3a in this process.
Our ability to develop targeted therapies against breast cancer is heavily dependent on a more detailed understanding of the molecular mechanism of EglN2-related breast tumorigenesis through generation and examination of accurate in vitro and in vivo model systems. This proposal will study the role of FOXO3a as the missing link by which EglN2 regulates Cyclin D1 and breast tumorigenesis. Successful completion of this proposal will motivate the development of EglN2 specific inhibitors as a means to induce FOXO3a to treat cancers, including breast cancers.
|Zheng, Xingnan; Zhai, Bo; Koivunen, Peppi et al. (2014) Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes Dev 28:1429-44|