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. High levels of Cyclin D1 have been observed in over 50% of mammary carcinomas. Downregulation of Cyclin D1 could inhibit breast tumor growth in vivo. Another ER target, EglN2 prolyl hydroxylase, has been found to regulate the expression of Cyclin D1, which places ER upstream of EglN2, and EglN2 upstream of Cyclin D1. In this proposal, I plan to use a combination of genetic and biochemical approaches to understand the role of EglN2 in ER signaling and mammary tumorigenesis. First, I will determine whether EglN2 loss will inhibit breast epithelia cell transformation in vitro. Next, I will introduce EglN2-downregulated breast cancer cells, which I found to slow breast cancer growth in vitro, into mice to test whether they slow down tumor growth in vivo. Lastly, I will study the mechanism by which EglN2 regulates Cyclin D1 expression. Together, these proposed studies describe an innovative way to downregulate Cyclin D1.
The data collected will greatly enrich our understanding of the role of EglN2 in Estrogen Receptor (ER) signaling and mammary tumorigenesis. Therefore, it will facilitate the development of effective drug targeting ER downstream signaling and provide a novel and potential successful therapeutic strategy for breast cancer treatment.
|Takada, Mamoru; Zhang, Weiguo; Suzuki, Aussie et al. (2017) FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A. Cancer Res 77:4881-4893|
|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|
|Zhang, Qing; Gu, Jinming; Li, Lianjie et al. (2009) Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer Cell 16:413-24|