About

Claudia Benavente, PhD, is an Associate Professor in the Department of Pharmaceutical Sciences and the Department of Developmental and Cell Biology at the University of California, Irvine. She is also affiliated with the Chao Family Comprehensive Cancer Center. Her research focuses on understanding the biological mechanisms underlying cancer and developmental processes, contributing to the advancement of therapeutic strategies. Dr. Benavente leads a research team that involves graduate students, postdoctoral fellows, and undergraduate students, working collaboratively to explore these scientific questions. Her lab has been active in engaging students at various levels, from high school to postdoctoral training, fostering a dynamic research environment dedicated to scientific discovery in cancer biology and developmental biology.

Research topics

• Cell biology
• Genetics
• Biology
• Neuroscience
• Anatomy
• Computational biology
• Biotechnology
• Cancer research

Selected publications

• Abstract 7400: UHRF1 as an epigenetic driver of tumorigenicity and immune evasion in triple negative breast cancer

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract Ubiquitin-like with PHD and RING Finger Domains 1 (UHRF1) is a multidomain epigenetic regulator essential for the maintenance of DNA methylation and repressive histone marks during cell division. As a downstream effector of the RB/E2F pathway, frequently deregulated in cancer, UHRF1 is aberrantly overexpressed in several malignancies, including triple-negative breast cancer (TNBC). Clinical datasets reveal that high UHRF1expression correlates with poor overall survival in TNBC, underscoring its clinical relevance.Using CRISPR/Cas9-mediated gene editing, we demonstrate that UHRF1 loss significantly impairs TNBC cell tumorigenicity. UHRF1-deficient TNBC cells exhibited reduced clonogenicity, migration, and invasion in vitro. In orthotopic xenograft models, tumors with low UHRF1 expression displayed significantly reduced growth and metastatic potential compared to controls. Transcriptomic profiling revealed that UHRF1 loss led to widespread depression of immune-related genes, suggesting that UHRF1 orchestrates an epigenetically repressed, immune-evasive state. To validate these findings in an immunocompetent context, Uhrf1 knockout (KO) TNBC cell lines were generated from mouse 4T1 cells.Consistent with human models, Uhrf1 KO cells displayed reduced tumorigenic potential and formed significantly smaller tumors in Balb/cJ mice. Importantly, Uhrf1 KO tumors showed increased infiltration of activated cytotoxic T cells (CD8+ CD44hi) and plasmacytoid dendritic cells (pDCs), alongside a higher cytotoxic-to-regulatory T cell ration, indicating an enhanced anti-tumor immune landscape following loss of UHRF1-mediated repression.Together, these results establish UHRF1 as a master epigenetic regulator linking the RB/E2F axis to tumor progression and immune modulation in TNBC. Targeting UHRF1-dependent chromatin regulation may represent a promising strategy to simultaneously suppress tumor growth and overcome immune evasion in aggressive breast cancers. Citation Format: Marina Suarez Pizarro, Ahhyun Kim, Jaime-Jean De La Torre, Xiyu Chen, Roberto Tinoco, Claudia A. Benavente. UHRF1 as an epigenetic driver of tumorigenicity and immune evasion in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7400.

  PublisherDOI

• UHRF1 is critical for tumor-promoting inflammation and tumorigenesis in retinoblastoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-07 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Retinoblastoma, the most common pediatric intraocular malignancy, arises from RB1 inactivation, leading to uncontrolled proliferation of retinal progenitor cells. Epigenetic dysregulation a key driver of retinoblastoma progression, yet the underlying mechanisms are poorly understood. UHRF1, a regulator of DNA methylation and chromatin remodeling, has been implicated in oncogenesis but its role in retinoblastoma has not been fully characterized. To investigate Uhrf1’s role in tumor initiation and progression, we generated a genetically engineered mouse model of retinoblastoma with conditional Uhrf1 knockout. Remarkably, Uhrf1 loss completely blocked tumor formation, despite persistent early oncogenic events. Transcriptomic and epigenomic profiling revealed that Uhrf1 is essential for tumor progression, facilitating oncogenic transcription, chromatin accessibility, and aberrant DNA methylation. Beyond its epigenetic role, we found Uhrf1 modulates the tumor immune microenvironment, promoting chemokine secretion and microglial infiltration, suggesting that Uhrf1 promotes immune cell recruitment. Mechanistically, Uhrf1 enhances chemokine expression through NF-κB signaling, establishing a novel connection between epigenetic regulation and tumor-associated immune responses. These findings establish Uhrf1 as a critical driver of retinoblastoma progression, essential for tumor maintenance but not initiation. By sustaining oncogenic transcriptional programs and shaping a pro-tumor immune microenvironment, Uhrf1 emerges as a promising therapeutic target for inhibiting tumor growth and immune evasion.

  PublisherOA PDFDOI

• Abstract 2985: UHRF1 drives small cell lung cancer progression and immune evasion via epigenetic regulation

  Cancer Research · 2025-04-21

  articleSenior author

  Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer, with a five-year survival rate of less than 8%. This poor prognosis stems primarily from rapid tumor growth, early metastasis, and an immunologically “cold” tumor microenvironment. A hallmark of SCLC is the near-universal inactivation of the RB transcriptional corepressor 1 (RB1), yet therapeutic advancements have been hindered by the lack of targetable oncogenic mutations. Our research has identified ubiquitin-like containing PHD and RING Finger domains 1 (UHRF1) as a direct downstream target of the RB pathway and a key protein overexpressed in RB-deficient cancers, including SCLC. Elevated UHRF1 expression correlates with poor survival outcomes in SCLC patients, but its specific role in disease progression remains poorly understood. We hypothesized that UHRF1 overexpression is critical for SCLC tumor progression. To test this hypothesis, we employed CRISPR-Cas9 and shRNA to disrupt UHRF1 expression in human SCLC cell lines. We assessed changes in tumor cell proliferation, clonogenicity, migration, and invasion in vitro, alongside primary tumor growth, metastasis, and survival in vivo. Additionally, we developed genetically engineered mouse models of SCLC to explore Uhrf1’s role of in tumor development, particularly its interaction with the immune microenvironment. Our findings reveal that UHRF1 overexpression drives a more aggressive tumor phenotype by promoting SCLC proliferation, angiogenesis, and maintaining an immune “cold” environment. Loss of UHRF1 in both human and mouse models led to significantly improved survival outcomes. These results underscore UHRF1’s critical role in SCLC progression and highlight its potential as therapeutic target. To elucidate the molecular mechanisms behind UHRF1’s oncogenic roles, we performed transcriptomic analysis using bulk RNA-seq, further validated by RT-qPCR. Upon UHRF1 KO, we observed significant gene expression changes, including downregulation of ST6GALNAC5 and upregulation of MAGEA4, RERG, and TGFBI. Pathway analysis suggests that UHRF1 modulates these downstream targets epigenetically, potentially through DNA methylation. In conclusion, our study identifies UHRF1 as an oncogenic driver in SCLC, facilitating tumor growth, metastasis, and immune evasion via epigenetic regulation. These findings provide a foundation for developing targeted therapies aimed at UHRF1 or its key downstream effectors to improve outcomes for SCLC patients. Citation Format: Yijun Gu, Claudia Benavente. UHRF1 drives small cell lung cancer progression and immune evasion via epigenetic regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2985.

  PublisherDOI

• USP7 inhibition perturbs proteostasis and tumorigenesis in triple negative breast cancer

  npj Breast Cancer · 2025-02-03 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT The deubiquitinase USP7 is a critical regulator of tumorigenesis, known for stabilizing the MDM2-p53 pathway. Emerging evidence highlights USP7’s p53-independent roles in proliferation and tumorigenesis. Triple negative breast cancers frequently inactivate p53 and this disease subtype remains difficult to treat and in need of new therapeutic options. Our study reveals that USP7 is upregulated in TNBC patient tumors. Importantly, genetic and pharmacologic USP7 inactivation impaired tumor progression in TNBC models. To explore USP7’s role in p53-mutant TNBCs, we performed deep quantitative proteomics across TNBC cell lines, identifying shared USP7 targets involved in cell proliferation, genome stability, and proteostasis. Acute USP7 inactivation allowed us to infer proximally controlled proteins which are likely direct targets. Surprisingly, many of the proteins downregulated by USP7 inhibition are E3 ubiquitin ligases. Thus, a key USP7 function in TNBC is to antagonize the degradation of ubiquitinating enzymes, since these enzymes are often susceptible to auto-ubiquitination and degradation. Notably, we identified TOPORS, a dual ubiquitin- and SUMO-ligase, among novel USP7 substrates. TOPORS interacts with the BRCA1-A DNA damage repair complex suggesting a USP7-TOPORS-BRAC1-A axis that might further explain the continued proliferation of genomically unstable TNBCs. Collectively, these data nominate USP7 as a potential therapeutic in TNBC.

  PublisherDOI

• Exploring the Impact of Exosomal Cargos on Osteosarcoma Progression: Insights into Therapeutic Potential

  International Journal of Molecular Sciences · 2024-01-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that OS-derived exosomes can drive pro-tumorigenic or anti-tumorigenic phenotypes by transferring specific cargos, including proteins, nucleic acids, and metabolites, to neighboring cells, significantly impacting the regulation of cellular processes. This review discusses the advancement of exosomes and their cargos in OS. We examine how these exosomes contribute to the modulation of cellular phenotypes associated with tumor progression and metastasis. Furthermore, we explore the potential of exosomes as valuable biomarkers for diagnostics and prognostic purposes and their role in shaping innovative therapeutic strategies in OS treatment development.

  PublisherOA PDFDOI

• Oncogenic Roles of UHRF1 in Cancer

  Epigenomes · 2024-07-01 · 24 citations

  reviewOpen accessSenior authorCorresponding

  Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential protein involved in the maintenance of repressive epigenetic marks, ensuring epigenetic stability and fidelity. As an epigenetic regulator, UHRF1 comprises several functional domains (UBL, TTD, PHD, SRA, RING) that are collectively responsible for processes like DNA methylation, histone modification, and DNA repair. UHRF1 is a downstream effector of the RB/E2F pathway, which is nearly universally deregulated in cancer. Under physiological conditions, UHRF1 protein levels are cell cycle-dependent and are post-translationally regulated by proteasomal degradation. Conversely, UHRF1 is overexpressed and serves as an oncogenic driver in multiple cancers. This review focuses on the functional domains of UHRF1, highlighting its key interacting proteins and oncogenic roles in solid tumors including retinoblastoma, osteosarcoma, lung cancer, and breast cancer. Additionally, current therapeutic strategies targeting UHRF1 domains or its interactors are explored, providing an insight on potential clinical applications.

  PublisherOA PDFDOI

• Landscape and Treatment Options of Shapeshifting Small Cell Lung Cancer

  Journal of Clinical Medicine · 2024-05-26 · 5 citations

  articleOpen accessSenior authorCorresponding

  Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy, notorious for its rapid tumor growth, early metastasis, and relatively "cold" immune environment. Only standard chemotherapies and a few immune checkpoint inhibitors have been approved for SCLC treatment, revealing an urgent need for novel therapeutic approaches. Moreover, SCLC has been recently recognized as a malignancy with high intratumoral and intertumoral heterogeneity, which explains the modest response rate in some patients and the early relapse. Molecular subtypes defined by the expression of lineage-specific transcription factors (ASCL1, NEUROD1, POU2F3, and, in some studies, YAP1) or immune-related genes display different degrees of neuroendocrine differentiation, immune cell infiltration, and response to treatment. Despite the complexity of this malignancy, a few biomarkers and targets have been identified and many promising drugs are currently undergoing clinical trials. In this review, we integrate the current progress on the genomic landscape of this shapeshifting malignancy, the characteristics and treatment vulnerabilities of each subtype, and promising drugs in clinical phases.

  PublisherOA PDFDOI

• Abstract 3180: Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma

  Cancer Research · 2024-03-22

  articleOpen access

  Abstract Glioblastoma multiforme (GBM) is the most aggressive primary malignant brain tumor in adults, with a poor prognosis that highlights a dire clinical need for innovative therapeutic interventions. Despite significant advances in diagnoses and multimodality therapies, the overall prognosis for patients with GBM remains poor, with a median survival time of 15-18 months. Therefore, there is an unmet medical need to develop alternative treatment strategies to improve clinical outcomes. Dysregulation of post-transcriptional control and translational machinery have been implicated in malignant tumor development. Cytoplasmic polyadenylation element binding proteins (CPEB1-CPEB4) are RNA-binding proteins that regulate poly(A) tail elongation of target mRNAs and subsequently contribute to phenotypic changes in cancer cells. Notably, a self-cleaving ribozyme was identified in the CPEB3 gene, but its role in cancer is wholly unexplored. Considering the role of CPEB3 as a tumor suppressor gene and the promotion of cancer progression through the downregulation of CPEB3, our hypothesis is that the CPEB3 ribozyme regulates CPEB3 expression, and its activity contributes to the progression of tumors. Using antisense oligonucleotides (ASOs) as an approach, we demonstrated that inhibition of CPEB3 ribozyme resulted in an increase of CPEB3 mRNA and protein expression. Blocking the CPEB3 ribozyme led to a significant reduction in cell proliferation, migration, and invasion in GBM cell lines. Gene set enrichment analysis (GSEA) revealed the downregulation of epithelial-mesenchymal transition (EMT), angiogenesis, and hypoxia gene sets in GBM cells treated with ASO compared to Ctrl-ASO. We further measured VEGFA mRNA and protein expression and found that ASO-treated GBM cells secreted significantly less VEGF in conditioned media. Inhibition of the CPEB3 ribozyme also mitigated the EMT process in GBM cells. Subsequently, ASO strategies were applied to patient-derived glioma stem cells (GSCs), representing a clinically relevant model for pre-clinical therapeutic intervention. We found that treatment of CPEB3 ribozyme ASO up-regulated CPEB3 mRNA and inhibited cell proliferation in GSCs. Furthermore, the combination of ASO and temozolomide chemotherapy exhibited a more pronounced decrease in GSCs proliferation compared to individual treatment alone. Collectively, this study highlights the significance of the CPEB3 ribozyme in GBM and explores therapeutic approaches focused on targeting CPEB3 in cancer. Citation Format: Claire Chen, Eric Wang, Lily Tong, Mehran Nikan, Daniela A. Bota, Claudia Benavente, Andrej Luptak. Suppression of the CPEB3 ribozyme modulates the progression of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3180.

  PublisherOA PDFDOI

• Abstract 569: Targeting UHRF1’s proteasomal destruction as a novel approach for small cell lung cancer treatment

  Cancer Research · 2024-03-22

  articleSenior author

  Abstract Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with a five-year survival rate of less than 8% due to rapid tumor growth, early metastasis, and a “cold” immune environment. Genetic alteration at the RB transcriptional corepressor 1 (RB1) is nearly universally present in SCLC patients. However, the therapeutic development was impeded by a lack of druggable oncogenic mutations. Studies in our laboratory identified ubiquitin-like, containing PHD and RING Finger domains 1 (UHRF1) as a critical protein overexpressed in many cancers with RB-pathway inactivation, including SCLC. Despite UHRF1 overexpression correlates with poor survival in SCLC patients, the roles of UHRF1 in SCLC progression remain to be elucidated. We hypothesized that UHRF1 overexpression is essential for SCLC tumor progression and can be targeted through endogenous proteasomal degradation. To define the role of UHRF1 in SCLC, we generated UHRF1 knockout and knockdown human SCLC cell lines. Using these mutants, we assessed changes in proliferation, clonogenicity, migration, and invasion capabilities. We report that UHRF1 overexpression present in human SCLC cell lines contributes to a more aggressive tumor presentation, affecting both tumor growth and metastasis. Besides human cell line models, we also generated genetically engineered mouse models of SCLC to study the role of Uhrf1 in tumor development, especially in an immune environment. Our results indicate that Uhrf1 overexpression promotes SCLC proliferation, angiogenesis, and pro-tumoral macrophage polarization, overall conditioning a tumor microenvironment that supports a more aggressive phenotype. Loss of Uhrf1 in this system results in a robust increase in overall survival. These results strongly support a critical role of UHRF1 in SCLC tumor progression and provide guidance for future SCLC therapeutics targeting UHRF1 or its key downstream effectors. One approach we apply is to utilize UHRF1’s endogenous degradative machinery by inhibiting its deubiquitinase USP7. In normal cells, UHRF1 abundance oscillates through cell cycle due to the regulation of ubiquitin machinery. USP7 cleaves ubiquitin marks on UHRF1, antagonizing UHRF1 degradation. We report that same as UHRF1, knocking out USP7 leads to decreased clonogenicity, migration, and invasion in human SCLC cell lines. Highly specific USP7 chemical inhibitors, XL-177A and FT671, were also tested and the same effects as USP7 knockout were observed. Collectively, our findings describe the oncogenic role of UHRF1 in SCLC proliferation, metastasis, and immune recognition and provide a therapeutic strategy of inhibiting USP7 for UHRF1 destruction. Citation Format: Yijun Gu, Claudia A. Benavente. Targeting UHRF1’s proteasomal destruction as a novel approach for small cell lung cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 569.

  PublisherDOI

• Abstract PR04: USP7 inhibitors prevent triple negative breast cancer metastasis by inducing UHRF1 protein degradation

  Cancer Research · 2024-02-01 · 1 citations

  articleSenior author

  Abstract Functional inactivation of RB1 occurs frequently in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype with poor clinical prognosis when tumors metastasize. Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is a key epigenetic regulator that is controlled by the RB-E2F pathway and is frequently overexpressed in many types of cancers, including TNBC. Using TCGA and METABRIC databases, we found that UHRF1 overexpression is negatively associated with breast cancer patient survival, including TNBC. Genetic ablation of UHRF1 using CRISPR/Cas9 in TNBC cell lines resulted in a robust decrease in tumorigenicity, including decreased cell clonogenicity (soft agar colony assay), migration (scratch wound healing assay), and invasion (Transwell assay) in vitro and decreased tumor growth and metastasis using orthotopic xenograft in vivo models. Despite strong evidence showing UHRF1 as a promising therapeutic target in several cancers, there is a current lack of UHRF1-specific inhibitors. To overcome this limitation, we explored targeting Ubiquitin-Specific Protease 7 (USP7), a deubiquitinase that prevents UHRF1 degradation, as a therapeutic strategy to trigger UHRF1 degradation. Here, we demonstrate that genetic inactivation or pharmacological inhibition of USP7 decreases TNBC tumor growth and metastasis in a UHRF1-degradation dependent manner. Phenocopying the effects of knocking out UHRF1, genetic ablation of USP7 using CRISPR/Cas9 in TNBC cell lines also resulted in significant decreases in cell clonogenicity, migration, and invasion in vitro. Intriguingly, mice bearing USP7 knockout tumors resulted in a far more robust decrease in tumor growth and absolute absence of metastatic disease. We established that many of the effects driven by USP7 ablation were mediated by the targeted degradation of UHRF1 by comparing vector control cell lines with UHRF1 knockout cells treated with the highly selective USP7 inhibitors, XL177A or FT671. In the absence of UHRF1, USP7 inhibitors showed no effects in cell migration and invasion in the three TNBC cell lines used in this study. Of promise, NSG mice bearing MDA-MB-231 tumors were recruited into vehicle or 50 mg/kg FT671 treatment groups and dosed daily via oral gavage for 20 days. For mice treated with FT671, we observed a significant decrease in tumor growth, with decreased UHRF1 levels in tumors, with minimal systemic toxicities. This study suggests that USP7 is a target with potential clinical relevance in suppressing tumor growth and metastasis in TNBC, and possibly other TP53-null cancers. These are promising results that present a novel opportunity for future clinical interventions for TNBC patients. Citation Format: Ahhyun Kim, Claudia Benavente. USP7 inhibitors prevent triple negative breast cancer metastasis by inducing UHRF1 protein degradation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR04.

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Recent grants

• NIH Grant K99CA178207

  NIH · $205k · 2015

• Genome instability and epigenetic deregulation in retinoblastoma and osteosarcoma

  NIH · $732k · 2013–2017

• Role of UHRF1 in osteosarcoma and its relationship to RB

  NIH · $2.4M · 2019–2025

Frequent coauthors

• Michael A. Dyer

  16 shared

• Stephanie Wu

  11 shared

• Loredana Zocchi

  University of California, Irvine

  8 shared

• Elaine L. Jacobson

  University of Arizona

  7 shared

• Jie Wu

  University of California, Irvine

  4 shared

• Yijun Gu

  Shanghai Advanced Research Institute

  4 shared

• Ahhyun Kim

  University of California, Irvine

  4 shared

• Ralph G. Meyer

  Utah State University

  3 shared

Labs

• BENAVENTE LABPI

Education

• B.S., Molecular Biotechnology Engineering

  Universidad de Chile

  2001

• M.S., Molecular Biotechnology Engineering

  Universidad de Chile

  2002

• Ph.D., Cancer Biology

  The University of Arizona

  2007

Awards & honors

• AACR-Aflac Career Development Award for Pediatric Cancer Res…
• NIH Pathway to Independence Award (2013–2017)
• Fulbright Scholar (2003–2005)