ArticleBreast cancer research : BCR2019
The p52 isoform of SHC1 is a key driver of breast cancer initiation.
Article in Breast cancer research : BCR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 45 citations in OpenAlex.
- Construction and validation of an EGFR-related risk signature identifiedTranslational cancer research · 2025Article
- The Role of p66Shc in Cancer: Molecular Mechanisms and Therapeutic Implications.Journal of cellular and molecular medicine · 2025Review
- FCGR2B knockdown alleviates diabetes-induced cognitive dysfunction by altering neuronal excitability.Molecular medicine (Cambridge, Mass.) · 2025Article
- Single-cell and spatial transcriptome analyses reveal tumor heterogeneity and immune remodeling involved in pituitary neuroendocrine tumor progression.Nature communications · 2025Article
- SHCBP1 drives tumor progression in triple-negative breast cancer.Frontiers in oncology · 2025Article
- Distribution of the p66Shc Adaptor Protein Among Mitochondrial and Mitochondria-Associated Membranes Fractions in Normal and Oxidative Stress Conditions.International journal of molecular sciences · 2024Article
- SHC1 serves as a prognostic and immunological biomarker in clear cell renal cell carcinoma: a comprehensive bioinformatics and experimental analysis.Scientific reports · 2024Article
- USP15, activated by TFAP4 transcriptionally, stabilizes SHC1 via deubiquitination and deteriorates renal cell carcinoma.Cancer science · 2024Article
- Bortezomib promotes the TRAIL-mediated killing of resistant rhabdomyosarcoma by ErbB2/Her2-targeted CAR-NK-92 cells via DR5 upregulation.Molecular therapy. Oncology · 2024Article
- The mitochondria-related gene risk mode revealed p66Shc as a prognostic mitochondria-related gene of glioblastoma.Scientific reports · 2024Article
- Therapeutic potential of SHCBP1 inhibitor AZD5582 in pancreatic cancer treatment.Cancer science · 2024Article
- Article
- Identification and validation of SHC1 and FGFR1 as novel immune-related oxidative stress biomarkers of non-obstructive azoospermia.Frontiers in endocrinology · 2024Article
- Article
- SERPINE1 and its co-expressed genes are associated with the progression of clear cell renal cell carcinoma.BMC urology · 2023Article
- The E3 ubiquitin ligase SOCS-7 reverses immunosuppression via Shc1 signaling in hepatocellular carcinoma.Laboratory investigation; a journal of technical methods and pathology · 2022Article
- A Data Science Approach for the Identification of Molecular Signatures of Aggressive Cancers.Cancers · 2022Article
- A New Thinking: Deciphering the Aberrance and Clinical Implication of IGF Axis Regulation Pattern in Clear Cell Renal Cell Carcinoma.Frontiers in immunology · 2022Article
- Pan-Cancer Study of SHC-Adaptor Protein 1 (SHC1) as a Diagnostic, Prognostic and Immunological Biomarker in Human Cancer.Frontiers in genetics · 2022Article
- SHC1 Promotes Lung Cancer Metastasis by Interacting with EGFR.Journal of oncology · 2022Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
backgroundSHC1 proteins (also called SHCA) exist in three functionally distinct isoforms (p46SHC, p52SHC, and p66SHC) that serve as intracellular adaptors for several key signaling pathways in breast cancer. Despite the broad evidence implicating SHC1 gene products as a central mediator of breast cancer, testing the isoform-specific roles of SHC1 proteins have been inaccessible due to the lack of isoform-specific inhibitors or gene knockout models.
methodsHere, we addressed this issue by generating the first isoform-specific gene knockout models for p52SHC and p66SHC, using germline gene editing in the salt-sensitive rat strain. Compared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. Rats were dosed with 7,12-dimethylbenz(a)anthracene (DMBA) by oral gavage to induce mammary tumors, and progression of tumor development was followed for 15 weeks. At 15 weeks, tumors were excised and analyzed by RNA-seq to determine differences between tumors lacking p66SHC or p52SHC.
resultsCompared with the wild-type (WT) rats, we found that genetic ablation of the p52SHC isoform significantly attenuated mammary tumor formation, whereas the p66SHC knockout had no effect. These data, combined with p52SHC being the predominant isoform that is upregulated in human and rat tumors, provide the first evidence that p52SHC is the oncogenic isoform of Shc1 gene products in breast cancer. Compared with WT tumors, 893 differentially expressed (DE; FDR < 0.05) genes were detected in p52SHC KO tumors compared with only 18 DE genes in the p66SHC KO tumors, further highlighting that p52SHC is the relevant SHC1 isoform in breast cancer. Finally, gene network analysis revealed that p52SHC KO disrupted multiple key pathways that have been previously implicated in breast cancer initiation and progression, including ESR1 and mTORC2/RICTOR.
conclusionCollectively, these data demonstrate the p52SHC isoform is the key driver of DMBA-induced breast cancer while the expression of p66SHC and p46SHC are not enough to compensate.
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