Dysregulation of mammary developmental processes have resulted in breast cancer development and progression. Thus, understanding normal mammary gland development is critical to understanding how cancer cells are initiated and maintained. Transcriptomic profiling of various mammary gland developmental phases, including virgin, pregnancy, lactation and involution, revealed distinct gene expression patterns associated at each stage. Pathway analysis predicted a role for transcription factors E2F1-4 during different stages of development. The importance of E2Fs in mammary development was confirmed by the defects observed in the mammary glands of mice deficient for various E2Fs.To examine if compensation occurs among activator E2Fs in the mammary gland, we analyzed mammary gland development in double E2F knockout mice. Our analysis revealed that compensation does occur among activator E2Fs in the mammary gland. However, this compensation appears to be very specific, as E2F2 can compensate for E2F1 but not E2F3 loss. Although the role of E2F1-4 has been characterized in mammary gland development, little is known about E2F5, an E2F demonstrating repressor activity. Using bioinformatic analysis, we predicted a role for E2F5 in terminal end bud differentiation and developmental stages. To further examine the role of E2F5 in normal mammary gland development, we generated a mammary-specific E2F5 knockout mouse model (E2F5CKO). Analysis of mammary gland development in E2F5CKO mice reveal only modest mammary gland defects. However, we found that E2F5CKO animals develop mammary tumors after a prolonged latency. Using transcriptomic profiling, we identified oncogenes that are dysregulated in E2F5CKO tumors, potentially contributing to tumorigenesis. Through these studies, we have identified a novel role of E2F5 as a tumor suppressor in breast cancer and further elucidated roles of E2Fs in mammary gland development.
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