Nature Genetics (IF: 29) | p53 Inactivation Drives Breast Cancer Brain Metastasis

Introduction

from breast cancer is associated with an extremely poor prognosis, yet the molecular mechanisms underlying its brain tropism have remained largely elusive. In a recent study published in Nature Genetics, a research team led by Uri Ben-David and Ronit Satchi-Fainaro at Tel Aviv University, Israel, identified p53 inactivation as a central driver of breast cancer brain metastasis. Mechanistically, loss of p53 function upregulates stearoyl-CoA desaturase 1 (SCD1) and enhances fatty acid metabolism, thereby providing critical metabolic support for tumor cell survival and proliferation within the brain microenvironment.

By integrating clinical data analyses, gene-edited cellular models, in vivo animal experiments, and metabolomics profiling, the study comprehensively delineates a brain metastasis–driving pathway characterized by "p53 inactivation → SCD1/FAS activation → fatty acid metabolic reprogramming." Importantly, the authors further demonstrate that inhibitors of fatty acid synthesis exhibit significant therapeutic efficacy against p53-deficient brain metastatic tumors, unveiling novel targets and precision treatment strategies for breast cancer brain metastasis.

Research Background

Breast cancer is the most common malignancy among women, and approximately 13% of patients develop brain metastases. Once brain metastasis occurs, patient survival is markedly shortened. The tumor suppressor p53, encoded by the TP53 gene, is the most frequently altered tumor suppressor in breast cancer. Its inactivation arises through mechanisms including genetic mutations and loss of the short arm of chromosome 17 (chr17p). However, the role of p53 dysfunction in organ-specific metastasis of breast cancer—particularly brain metastasis—has remained unclear.

The brain microenvironment is characterized by limited lipid availability, whereas brain metastatic tumor cells frequently exhibit metabolic features marked by enhanced fatty acid synthesis (FAS). Astrocytes, as a critical cellular component of the brain microenvironment, play an essential role in modulating tumor–microenvironment interactions; however, their contribution to tumor cell adaptation and regulation of fatty acid metabolism in brain metastasis has yet to be fully elucidated.

Research Objective

This study aims to elucidate the role and molecular mechanisms of p53 inactivation in breast cancer brain metastasis, to define its association with fatty acid metabolism, and to evaluate the therapeutic potential of fatty acid synthesis-related targets in this context.

Research Methods

• Clinical data analysis: Genomic and transcriptomic datasets from multiple clinical cohorts, including TCGA and METABRIC, were integrated to assess the association between p53 inactivation and brain metastasis in breast cancer.
• Cell line model generation: Isogenic breast cancer cell lines with wild-type (WT) or inactivated p53 (knockout or mutant) were generated using CRISPR-Cas9 technology in EMT6 and CAL51 backgrounds. In addition, SCD1 knockout cell lines were established.
• In vivo models: Brain metastasis models were established via intracardiac injection, while intracranial injection was used to evaluate tumor growth. Tumor burden was longitudinally monitored by MRI. Cell competition assays were performed to validate the brain-specific pro-metastatic effect of p53 inactivation.
• Metabolic analyses: Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were employed to quantify fatty acid composition and metabolite abundance. Metabolic flux was traced using stable isotope labeling (¹³C-palmitate and ¹³C-glutamate). Astrocyte-conditioned medium (ACM) was used to model interactions between astrocytes and tumor cells.
• Mechanistic studies: CUT&Tag, chromatin immunoprecipitation (ChIP), and co-immunoprecipitation (Co-IP) assays were conducted to dissect p53-mediated regulation of SCD1, DEPDC1, and SREBP1. RNA interference (siRNA) was used to knock down target genes to functionally validate the pathway.
• Drug sensitivity assays: The therapeutic efficacy of SCD1 inhibitors (SW203668, A939572) and the FASN inhibitor C75 was evaluated in cell-based assays, organoid models, and in vivo systems.

Research Workflow

• Clinical association validation: Multi-cohort clinical data were analyzed to confirm the significant enrichment of p53 inactivation in breast cancer brain metastases and to establish p53 loss as a predictive indicator of brain metastasis risk.
• Functional validation: Cell-based and in vivo experiments demonstrated that p53 inactivation specifically enhances the brain metastatic capacity of breast cancer cells and confers a growth advantage within the brain.
• Microenvironmental interaction analysis: Astrocytes were shown to promote the proliferation, migration, and survival of p53-inactivated tumor cells through the secretion of key metabolites, including palmitate and glutamate.
• Metabolic mechanism dissection: p53 inactivation was found to upregulate CD36 (fatty acid uptake) and SCD1 (fatty acid synthesis), thereby enhancing tumor cell utilization and de novo synthesis of fatty acids within the lipid-poor brain microenvironment.
• Regulatory pathway elucidation: p53 was demonstrated to directly bind the SCD1 promoter while indirectly regulating SCD1 expression through repression of the co-activator DEPDC1, forming a dual-layer regulatory network.
• Therapeutic potential assessment: The efficacy of fatty acid synthesis inhibitors was validated in cell culture systems, organoid models, and animal models, demonstrating targeted therapeutic activity against p53-deficient brain metastatic tumors.

p53 Inactivation Drives Brain Metastasis (BM) Through Adaptive Reprogramming of Fatty Acid Metabolism

Key Findings

• p53 inactivation is highly associated with breast cancer brain metastasis: Clinical analyses revealed that 100% of breast cancer brain metastases exhibit p53 inactivation, either through TP53 mutation or loss of chromosome 17p (chr17p). The frequency of p53 loss was significantly higher in brain metastatic lesions than in matched primary tumors or metastases at other anatomical sites. Moreover, primary tumors harboring p53 inactivation displayed a markedly increased propensity to develop brain metastases. Notably, this association was conserved across multiple cancer types, indicating a broader role for p53 loss in brain metastatic tropism.

  

  Figure 1. Genomic and transcriptomic analyses of clinical datasets reveal a marked enrichment of TP53 perturbations in breast cancer brain metastases (BCBM)

• p53 inactivation promotes breast cancer brain metastasis and intracranial tumor growth: In intracardiac injection models, p53-inactivated cells exhibited a markedly higher incidence of brain metastasis (12/13 mice) compared with wild-type counterparts (2/11 mice). Following intracranial injection, p53-deficient cells formed significantly larger tumors with enhanced proliferative capacity, and this growth advantage was maintained irrespective of host immune status.

  

  Figure 2. p53 inactivation enhances basement membrane invasion and tumor growth in TP53-WT breast cancer cells

• Astrocytes enhance the metabolic adaptation of p53-inactivated tumors: Astrocyte-secreted metabolites, including palmitate (PA) and glutamate, promote tumor cell proliferation and migration in a p53-dependent manner. p53-deficient cells upregulate CD36 to increase fatty acid uptake and exhibit greater tolerance to high concentrations of PA, highlighting a metabolic adaptation that facilitates survival and growth in the brain microenvironment.

  

  Figure 3. Astrocyte-derived signals promote proliferation, migration, and survival of breast cancer cells via a p53-dependent mechanism

  

  Figure 4. Upregulation of CD36 and enhanced fatty acid uptake promote proliferation and migration of p53-deficient breast cancer cells

• p53 inactivation drives upregulation of key fatty acid synthesis genes: Loss of p53 markedly increases the expression of fatty acid synthesis-related genes, including SCD1 and FASN. SCD1 catalyzes the conversion of palmitate into monounsaturated fatty acids (MUFAs), providing essential lipid resources to support rapid tumor cell proliferation.

  

  Figure 5. SCD1-mediated fatty acid synthesis drives brain metastasis of p53-deficient breast cancer cells

  CUT&Tag analysis confirms that p53 directly binds the promoters of SCD1 and SREBP1, while indirectly regulating fatty acid synthesis by repressing DEPDC1, a co-activator of SREBP1.

  

  Figure 6. Molecular mechanism by which p53 regulates fatty acid synthesis in breast cancer cells

• SCD1 is a key mediator of p53 inactivation–driven brain metastasis: Knockout of SCD1 completely abrogated the intracranial growth advantage conferred by p53 loss, resulting in a 57% reduction in tumor volume. Conversely, supplementation with SCD1-derived products, such as palmitoleic acid and oleic acid, recapitulated the pro-metastatic effects of p53 inactivation.

  

  Figure 7. SCD1 is a key mediator of p53 inactivation–driven brain metastasis

• Fatty acid synthesis inhibitors are effective against p53-deficient tumors: p53-inactivated cells exhibited markedly higher sensitivity to SCD1 and FASN inhibitors compared with wild-type cells. In animal models, SCD1 inhibition significantly reduced the volume of p53-deficient brain metastases. Moreover, patient-derived brain metastasis organoids also showed high responsiveness to SCD1 inhibitors, highlighting the translational potential of targeting fatty acid synthesis in p53-deficient tumors.

  

  Figure 8. Fatty acid synthesis (FAS) represents a targetable vulnerability in p53-deficient breast cancer brain metastases (BCBM)

Significance and Innovations

• Theoretical innovation: This study is the first to establish p53 inactivation as a central driver of breast cancer brain metastasis. It uncovers a non-cell-autonomous regulatory network—“p53 loss-astrocyte interaction-fatty acid metabolic reprogramming”—providing a new paradigm for understanding organ-specific metastatic metabolic adaptation.
• Mechanistic breakthrough: The research elucidates a dual-layer regulatory mechanism by which p53 controls fatty acid synthesis, involving both direct promoter binding and indirect regulation via co-activator repression. Importantly, SCD1 is identified as a critical metabolic node linking p53 inactivation to brain metastasis.
• Clinical relevance: The findings establish p53 inactivation as a predictive biomarker for breast cancer brain metastasis, enabling patient stratification. Furthermore, fatty acid synthesis targets such as SCD1 demonstrate therapeutic potential for p53-deficient brain metastases, with available inhibitors offering a promising path for rapid preclinical-to-clinical translation.

Summary

Through integrated clinical data analysis, functional experiments, and mechanistic studies, this research establishes p53 inactivation as a critical driver of breast cancer brain metastasis. p53 loss enhances tumor cell metabolic adaptation to the brain microenvironment by directly and indirectly regulating fatty acid synthesis–related genes such as SCD1, while astrocyte-secreted metabolites further amplify this effect.

The study not only uncovers a novel molecular mechanism underlying breast cancer brain metastasis, but also demonstrates the therapeutic potential of fatty acid synthesis inhibitors against p53-deficient brain metastatic tumors. These findings provide a solid theoretical foundation for risk prediction and precision therapy in breast cancer brain metastasis, and identify actionable metabolic targets for translational applications.

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Reference

Laue K, Pozzi S, Zerbib J, Bertolio R, Eliezer Y, Cohen-Sharir Y, Winkler T, Caputo M, Ricci AA, Adler L, Khoury R, Longobardi G, Slutsky R, Leikin-Frenkel AI, Ovadia S, Lange K, Rustighi A, Piazza S, Sacconi A, Magesh RY, Keller FN, Berthelet J, Schäffer A, Saad R, Israeli Dangoor S, Szczepanowska K, Barshack I, Liao Y, Malitsky S, Brandis A, Broggini T, Czabanka M, Shi W, Merino D, Watson EV, Blandino G, Erez A, Ashery-Padan R, Medyouf H, Bertero L, Del Sal G, Satchi-Fainaro R, Ben-David U. p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism. Nat Genet. 2025 Dec 29. doi: 10.1038/s41588-025-02446-1. Epub ahead of print. PMID: 41461910.