Explanations of tumor suppression tend to center on a single gene, and p53 deserves much of that attention. As a transcription factor, it turns other genes on and off, and it oversees several of the most basic functions inside a cell. p53 also has two close relatives, p63 and p73.
A body of work led by Dr. Elsa R. Flores, a Senior Member in the Department of Molecular Oncology in the Division of Discovery Science at Moffitt Cancer Center in Tampa, Florida, has focused on what those relatives actually do. What that work has found recasts the p53, p63, and p73 family as a system, which carries practical weight: when p53 itself is lost or mutated, its relatives are still present.
A Family, Not a Single Gene
The p53 family is made up of three related genes: p53, p63, and p73. Shared structural features and overlapping functions partly explain why researchers took so long to see the family as a system instead of as one gene with two lesser cousins.
Work on that question anchors her laboratory in the Department of Molecular Oncology at Moffitt Cancer Center in Tampa, and it falls within the Cancer Biology and Evolution Program, one of the research programs organized under Moffitt’s NCI Cancer Center Support Grant.
The single-gene view shaped drug development. Because p53 is a transcription factor governing broad programs of cellular behavior rather than a discrete enzyme or receptor, drug designers have had nothing obvious to grab onto, and the gene has been labeled “undruggable” for decades.
Research from the laboratory of Elsa R. Flores has used that limitation as a point of departure. If the central gene can’t be targeted directly, the next question is what else in the family, or downstream of it, might be. Getting at that question meant separating the family members in the lab, a harder task than it sounds. p63 and p73 each produce multiple isoforms, variant forms of the same gene with different properties, and studying either gene as a whole blurs those forms together.
Her Moffitt laboratory built a collection of isoform-specific conditional knockout mouse models, allowing individual family members and individual isoforms to be switched off separately and their effects observed in isolation. The same engineering bent runs through her teaching, and she holds a professorship in the Departments of Oncologic Sciences and Biomedical Engineering at the University of South Florida Health Morsani College of Medicine.
What Dr. Elsa R. Flores Has Shown About p63 and p73
The central finding from that work is that p63 and p73, along with their isoforms, suppress tumor formation and metastasis across a range of tissues. Both genes act as tumor suppressors in their own right, with no need to wait on p53, and the research behind this has appeared over more than a decade in journals including Nature, Cancer Cell, Nature Communications, Oncogene, and Cancer Research.
The mechanism adds another layer. These genes exert their tumor-suppressive effects at least partly through the transcriptional regulation of genes involved in microRNA biogenesis, the cellular process that produces small regulatory RNA molecules. Some of their power against cancer, then, comes from controlling the machinery that makes other regulators, which carries their influence past protein-coding targets and into the cell’s regulatory RNA. This regulatory role bears directly on metastasis, and the same body of work ties the two together.
A metastatic tumor has done more than grow; its cells have picked up a set of capabilities they lacked before. A suppressor acting at the level of gene regulation is positioned to block several of those capabilities at once instead of one at a time.
Beyond Cancer: Stem Cells, Metabolism, and Aging
Some of the less expected findings concern what these genes do outside of cancer altogether. p63 helps maintain adult stem cell populations, according to work published in Cell Stem Cell in 2009, and that research also linked p63 to aging. Later papers, among them a 2014 study in PNAS, built on the stem cell findings.
A metabolic dimension came into view around the same time. p63 regulates the transcription of metabolic programs tied to longevity, a connection developed in Cell Metabolism in 2012 and in Nature in 2015. Members of the family also play roles in germline embryonic stem cells and in the generation of induced pluripotent stem cells, the reprogrammed cells now used as a standard tool across biology.
None of this counts as cancer research on its face, but it matters for cancer all the same. A tumor under pressure from a drug leans on exactly these capabilities, stem cell maintenance and metabolic flexibility. One that can shift its metabolism or rebuild itself from a hardy subpopulation has more ways to survive than a simpler tumor. The genes that govern those capabilities in healthy tissue are the ones a tumor subverts, which helps explain why some tumors stop responding to treatment.
The Regulatory Layer: Non-Coding RNA and Super Enhancers
More recent work has moved further into the parts of the genome that don’t code for proteins. Long non-coding RNAs are transcribed from DNA without ever becoming proteins, and they influence which genes are active. Research from the Flores laboratory published in Nature Communications in 2020 identified an oncogenic long non-coding RNA regulated by TAp63, one of the p63 isoforms, and showed that targeting it interferes with activation of Akt, a signaling protein central to cell survival, and with resistance to multiple targeted cancer therapies.
A companion line of work, published in Nature Communications in 2022, linked the family to super enhancers, stretches of DNA that drive high-level gene expression. Both lines of research describe genes whose reach goes well beyond the textbook image of a tumor suppressor stopping cell division, placing them in a regulatory layer that decides which programs a cell is able to run.
This is also the practical payoff of the undruggable problem. A target that resists direct pharmacological attack may still be reachable through the RNA molecules it regulates or the enhancers it controls, which is much of what “undruggable” actually means in cancer research and why the label is not a verdict.
Where the Family Points Next
The current work reaches into the tissue surrounding tumors. Research in p53 mutant cancers has pointed to a role for TAp73 in mediating anti-tumor immunity through the regulation of lipid metabolism in the tumor microenvironment.
The suggestion is that a tumor can change the metabolic conditions around it enough to dampen the immune response it would otherwise meet, with a p53 family member positioned in the middle of that exchange.
These pathways are being studied as the basis for new approaches to p53 mutant lung adenocarcinoma, including tumors that no longer respond to KRAS inhibitors. That work sits within an NCI-funded program project grant on metabolic vulnerabilities in lung cancer, and it draws on freshly excised patient tumor samples available at Moffitt, the NCI-designated comprehensive cancer center in Tampa.
Across her research on translational oncology, the argument stays consistent: p53, p63, and p73 work as one system. When p53 is lost, its relatives remain in place and keep regulating overlapping programs, and the layers they act on (non-coding RNA, enhancers, metabolism, and the immune environment) are layers a drug may be able to reach. That offers a more promising path than waiting for someone to crack p53 directly.
