Deregulation of embryonic transcription factors in human epithelial cancers: new perspectives in breast and liver tumors

Carcinogenesis is commonly referred to as a multi-step process in which normal cells develop progressively into hyperplasia, carcinoma in situ, invasive cancer and metastasis. Several evidences indicate that transcription factors, which act as master regulators of embryonic development, may play a central role in this pathologic process. Indeed, growing evidence suggests that cancer cells often reactivate latent developmental programs in order to efficiently execute the multi-step process of tumorigenesis. Reminiscent of their function during development, embryonic transcription factors regulate changes in gene expression that promote tumor cell growth, cell survival and motility, as well as a morphogenetic process called epithelial-mesenchymal transition (EMT), which is implicated in both metastasis and tumor recurrence. Because of their pivotal roles in tumor progression, these factors represent valuable new biomarkers for cancer detection as well as promising new targets for alternative anti-cancer therapies. The present doctoral work explores the role of embryonic transcription factors deregulation in epithelial cancers and their therapeutic implications in the frontiers of precision oncology. More specifically, the first project identified MDM2 as a specific synthetic lethal partner of GATA3, an embryonic master regulator of the mammary gland often mutated in estrogen receptor-positive breast cancers. The second project identified the homeobox transcription factor HOXA13 as a novel oncogene, whose overexpression results in hepatocarcinogenesis in mice through the induction of chromosomal instability.