Control of Cyclin D1 and Breast Tumorigenesis by the EgIN2 Prolyl Hydroxylase

2-Oxoglutarate-dependent dioxygenases, including the EgIN prolyl hydroxylases that regulate HIF, can be inhibited with drug-like molecules. EgIN2 is estrogen inducible in breast carcinoma cells and the lone Drosophila EgIN interacts genetically with Cyclin D1. Although EgIN2 is a nonessential gene, we found that EgIN2 inactivation decreases Cyclin D1 levels and suppresses mammary gland proliferation in vivo. Regulation of Cyclin D1 is a specific attribute of EgIN2 among the EgIN proteins and is HIF independent. Loss of EgIN2 catalytic activity inhibits estrogen-dependent breast cancer tumorigenesis and can be rescued by exogenous Cyclin D1. EgIN2 depletion also impairs the fitness of lung, brain, and hematopoietic cancer lines. These findings support the exploration of EgIN2 inhibitors as therapeutics for estrogen-dependent breast cancer and other malignancies.