In the post-genomic era, many gene families have been identified. These genes can have overlapping and independent functions. The existence of redundant functions in gene families has made diseases like cancer challenging to treat and cure. The focus of The Flores Laboratory is to understand the intricacy of the p53 family of genes, p53, p63, and p73, in cancer using mouse genetics and biochemical approaches.
The goal of our work is to gain a global understanding of the complex functions of this gene family in cancer and to facilitate the design of targeted therapies for cancer patients with alterations in this family of genes. This type of research can be applied to other families of genes with redundant and unique functions in an effort to make significant progress in curing diseases like cancer.
Given the structural and functional similarity of p63 and p73 to p53, the early assumption was that these new family members were also tumor suppressor genes. The functions of p63 and p73 are not that simple due to the existence of isoforms with opposing functions including transactivation competent (TA) isoforms and those lacking the transactivation domain (ΔN). To determine the functions of these isoforms, my laboratory has generated conditional knock out mouse models that allow the deletion of the TA or ΔN isoforms of p63 or p73. Using these mouse models, we have unveiled previously unrecognized functions of p63 and p73 in apoptosis (Flores et al., Nature, 2002), DNA repair (Lin et al., PLoS Gen, 2009), and the suppression of tumorigenesis and metastasis (Flores et al., Cancer Cell, 2005; Su, Chakravarti et al., Nature, 2010).
Importantly we found that TAp63 is a critical suppressor of cancer metastasis in breast, lung, and skin cancers using mouse models and tumors from human patients (Su, Chakravarti et al., Nature, 2010). TAp63 suppresses metastasis by transcriptional regulation of Dicer and microRNAs (Su, Chakravarti et al., Nature, 2010). Current experiments using these novel mouse models are aimed at understanding the transcriptional network regulated by the isoforms of p63 and p73 in anti-tumorigenic pathways using high through put ChIP-Seq and RNA-Seq.
The understanding of the biology of stem cells is critical for the fields of cancer biology and regenerative medicine. p63 has been shown to play critical roles in skin morphogenesis. We have found that the tumor suppressor, TAp63, maintains adult stem cells within the skin in quiescence. In the absence of TAp63, these stem cells hyperproliferate, accumulate DNA damage, and senesce prematurely, leading to a premature aging phenotype in TAp63 deficient mice (Su et al. Cell Stem Cell, 2009). We are currently investigating the roles of TAp63 in cancer stem cells, and the functions of the other p53 family members in adult and cancer stem cells.
Metabolism and cancer are an area of intense research. Cancerous cells alter their metabolism to survive and flourish under conditions of limiting nutrients as the tumor grows. We have found that TAp63 deficient mice develop metabolic disorders. We are currently working to understand how these changes in metabolism lead to the tumor and metastatic phenotype of the TAp63 deficient mice.