Although the pivotal role of p53 in tumor suppression remains unchallenged, the role of its family members, p63 and p73 in normal cell function and tumorigenesis is far from certain. Structural similarities and functions of the p53 family of proteins connect them in similar signaling pathways, in both collaborative and antagonistic interactions;however, in vivo models suggest a role for both p63 and p73 in p53-independent developmental and differentiation processes. In particular, p63-null mice lack an epidermis and related structures such as mammary and prostate glands. Interestingly, p63 is expressed in the basal layer of several epithelial tissues such as skin, breast and prostate, and is overexpressed in many squamous and basal-like carcinomas. Evidence suggests that p63 may function in tumors in part through interaction with p73, which is also overexpressed in many human tumors. The goal of the proposed studies is to determine the roles of p63 and p73 in cell metabolism and survival as well as epithelial-mesenchymal crosstalk and transition, and to discover how these roles are deregulated during tumorigenesis. Through generation and integration of comprehensive chromatin immunoprecipitation and microarray data sets, we identified numerous novel p63 and p73 target genes. Based on our findings, we propose the following interrelated hypotheses: (i) p63 and p73 regulate the transcription of unique or shared target genes involved in cell metabolism and survival as well as epithelial-mesenchymal cross-talk and transition;and, (ii) loss of proper p63 and p73 activity will lead to altered cell survival and function resulting in developmental abnormalities or tumorigenesis, depending on the biological time point of dysfunction. These hypotheses will be tested through the following Specific Aims: (1) To analyze select novel target genes uniquely or coordinately regulated by p63 and p73. We will determine the role of these target genes in biologically relevant endpoints downstream of p63 and p73 signaling using organotypic model systems;(2) To analyze p63 and p73 protein complexes and a newly identified protein that interacts with these family members;and (3) To analyze mice with conditional, tissue-specific knock-out of p73. The mice will be characterized in terms of organ and metabolic function and response to stress. The effect of tissue-specific knockout of p63, p73, and p53, alone or in combination, in the mammary gland will be studied to determine the separate or coordinate roles of the family members in adult tissue function, and susceptibility to tumorigenesis. The importance of understanding p63 and p73 regulation and function is underscored by the deregulation of the p53 family in human tumors and the expectation that a mechanistic understanding of the p63 and p73 signaling axes in cancer will translate to therapeutic benefit for cancer patients.
While p53 has been extensively characterized as a tumor suppressor, it has been more difficult to determine if its family members, p63 and p73 play a similar role. In the proposed studies, we will employ genetically engineered cell and mouse model systems to determine the roles of p63 and p73 in cell metabolism and survival as well as epithelial-mesenchymal crosstalk and transition, and to discover how these roles are deregulated during tumorigenesis. It is essential to decipher the role of these proteins in both normal cell function and during tumorigenesis in order to design more effective anti- cancer therapies that will target the majority of human tumors that have a defective p53 family signaling axis.
|Santos Guasch, Gabriela L; Beeler, J Scott; Marshall, Clayton B et al. (2018) p73 Is Required for Ovarian Follicle Development and Regulates a Gene Network Involved in Cell-to-Cell Adhesion. iScience 8:236-249|
|Jovanovi?, Bojana; Mayer, Ingrid A; Mayer, Erica L et al. (2017) A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Clin Cancer Res 23:4035-4045|
|Shaver, Timothy M; Lehmann, Brian D; Beeler, J Scott et al. (2016) Diverse, Biologically Relevant, and Targetable Gene Rearrangements in Triple-Negative Breast Cancer and Other Malignancies. Cancer Res 76:4850-60|
|Lehmann, Brian D; Jovanovi?, Bojana; Chen, Xi et al. (2016) Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One 11:e0157368|
|Marshall, Clayton B; Mays, Deborah J; Beeler, J Scott et al. (2016) p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network. Cell Rep 14:2289-300|
|Lehmann, Brian D; Bauer, Joshua A; Schafer, Johanna M et al. (2014) PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 16:406|
|Balko, Justin M; Giltnane, Jennifer M; Wang, Kai et al. (2014) Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 4:232-45|
|Chen, Xi; Li, Jiang; Gray, William H et al. (2012) TNBCtype: A Subtyping Tool for Triple-Negative Breast Cancer. Cancer Inform 11:147-56|
|Lehmann, Brian D; Bauer, Joshua A; Chen, Xi et al. (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750-67|
|Rosenbluth, Jennifer M; Mays, Deborah J; Jiang, Aixiang et al. (2011) Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis. Proc Natl Acad Sci U S A 108:2076-81|
Showing the most recent 10 out of 29 publications