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Background <p>Breast cancer (BRCA) is a typical females’ malignant tumors. Ubiquitin-proteasome system (UPS) is a critical pathway for pathogenesis of BRCA. Activation of UPS is determined by SKP1–cullin 1–F-box protein (SCF) E3 ligase complexes. F-Box Protein 2 (FBXO2), a pivotal member of F-box proteins family, is associated with UPS. FBXO2 has attracted increasing attention in various cancers, yet its relationship with many cancer types is still unclear. Therefore, systematic research on FBXO2 and pan-cancer is very important for understanding BRCA progression and drug resistance.</p> Method <p>Transcriptome expression data of 33 cancer types were acquired from the Cancer Genome Atlas (TCGA) database. Wilcoxon test was performed to estimate the molecular characteristic of FBOX2 across human pan-cancer analyses. To confirmed the relationship between FBXO2 and BRCA, mendelian randomization (MR) was conducted. Kaplan–Meier (KM) analyses was used to evaluated the survival features of FBXO2. Additionally, protein and methylation level of FBXO2 were examined using Wilcoxon test. Single-cell sequence analysis was further applied to confirm the importance of FBXO2. The underlying mechanism of FBXO2 was explored from various perspectives, including gene function, immune checkpoint and tumor microenvironment. Finally, stable FBXO2-knockdown and overexpression models in MDA-MB-231 and MCF-7 were established, and functional assays including CCK-8, Transwell, and wound healing experiments were conducted to validate the role of FBXO2 in vitro.</p> Result <p>Our pan-cancer analysis revealed that FBXO2 was up-regulated in multiple cancer types, but was significantly down-regulated in BRCA. MR analysis confirmed a caused relationship between reduced FBXO2 expression and increased BRCA risk. Consistent with transcriptional findings, FBXO2 protein levels were also decreased in BRCA. KM analysis indicated that low FXBO2 expression was associated with poor overall survival (OS) and recurrence free survival (RFS) in BRCA patients. Single-cell sequence analysis further revealed that FBXO2 obviously enriched in malignant epithelial cells. In vitro functional experiments demonstrated that knockdown of FBXO2 significantly promoted cell proliferation, migration and invasion, whereas its overexpression suppressed these malignant phenotypes in BRCA.</p> Conclusion <p>In conclusion, our comprehensive analysis revealed that FBXO2 plays a critical tumor-suppression role in BRCA, with its down-regulation contributing to poor prognosis. Furthermore, FBXO2 was implicated in immune regulation and tumor microenvironment remodeling. Our findings provided novel insights into the pathogenesis of BRCA.</p>

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Integrated mendelian randomization and bioinformatics approach unveiling the immunological and prognostic significance of FBXO2 in breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月22日

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  • Rongzhi Huang,
  • Zhibai Chen,
  • Min Mao,
  • Shenglian Lai,
  • Jiehua Li

摘要

Background

Breast cancer (BRCA) is a typical females’ malignant tumors. Ubiquitin-proteasome system (UPS) is a critical pathway for pathogenesis of BRCA. Activation of UPS is determined by SKP1–cullin 1–F-box protein (SCF) E3 ligase complexes. F-Box Protein 2 (FBXO2), a pivotal member of F-box proteins family, is associated with UPS. FBXO2 has attracted increasing attention in various cancers, yet its relationship with many cancer types is still unclear. Therefore, systematic research on FBXO2 and pan-cancer is very important for understanding BRCA progression and drug resistance.

Method

Transcriptome expression data of 33 cancer types were acquired from the Cancer Genome Atlas (TCGA) database. Wilcoxon test was performed to estimate the molecular characteristic of FBOX2 across human pan-cancer analyses. To confirmed the relationship between FBXO2 and BRCA, mendelian randomization (MR) was conducted. Kaplan–Meier (KM) analyses was used to evaluated the survival features of FBXO2. Additionally, protein and methylation level of FBXO2 were examined using Wilcoxon test. Single-cell sequence analysis was further applied to confirm the importance of FBXO2. The underlying mechanism of FBXO2 was explored from various perspectives, including gene function, immune checkpoint and tumor microenvironment. Finally, stable FBXO2-knockdown and overexpression models in MDA-MB-231 and MCF-7 were established, and functional assays including CCK-8, Transwell, and wound healing experiments were conducted to validate the role of FBXO2 in vitro.

Result

Our pan-cancer analysis revealed that FBXO2 was up-regulated in multiple cancer types, but was significantly down-regulated in BRCA. MR analysis confirmed a caused relationship between reduced FBXO2 expression and increased BRCA risk. Consistent with transcriptional findings, FBXO2 protein levels were also decreased in BRCA. KM analysis indicated that low FXBO2 expression was associated with poor overall survival (OS) and recurrence free survival (RFS) in BRCA patients. Single-cell sequence analysis further revealed that FBXO2 obviously enriched in malignant epithelial cells. In vitro functional experiments demonstrated that knockdown of FBXO2 significantly promoted cell proliferation, migration and invasion, whereas its overexpression suppressed these malignant phenotypes in BRCA.

Conclusion

In conclusion, our comprehensive analysis revealed that FBXO2 plays a critical tumor-suppression role in BRCA, with its down-regulation contributing to poor prognosis. Furthermore, FBXO2 was implicated in immune regulation and tumor microenvironment remodeling. Our findings provided novel insights into the pathogenesis of BRCA.