P53 family members regulate the Otx1 gene expression in differentiation of breast cancer stem cells and in mammary gland development.

Tp53, Tp63 and Tp73 family members encode for transcription factors which play a key role in control of the genome integrity inducing cell-cycle arrest, senescence, apoptosis or cell differentiation. They take a part in cell stress response and in tumor suppression (De Young MP and Ellisen LW, 2007). Wild type p53 protein is a growth modulator and its inactivation is a critical event in malignant transformation (Gasco M, 2002). It has been recently demonstrated that p53 has developmental and differentiation functions (Hu W, 2008). Indeed an over-expression of p53 in tumor cells induces asymmetrical division avoiding a self-renewal of cancer stem cells (CSCs) and promoting their differentiation (Cicalese A, 2009). In this study 43 human ductal and lobular invasive breast carcinomas have been analyzed for the expression of p53, p63, p73 and a pool of non-clustered homeobox genes. The homeogenes play a crucial role in embryogenesis, regulating cell differentiation and proliferation (Pagani IS, 2010). They are expressed in adult mammary gland and when deregulated, are involved in breast cancer (Lewis MT, 2000). We demonstrated that the Otx1 homeogene is transcribed in breast cancer, in CSCs differentiation and in adult mammary gland development. We established that the p53 and p73 proteins directly induce the Otx1 expression by acting on its promoter. Otx1 has been described as a critical molecule for axon refinement in corticogenesis (Zhang YA, 2002), and its activity in breast cancer suggests a synergistic function with p53 and p73 in CSCs differentiation. In adult mammary gland development the Otx1 expression is not regulated by p53, but is correlated with the expression of Tp73 in lactation and in regression. This suggests that in physiological conditions Otx1 is regulated by p73, while in the tumors p53 regulates its expression.