ArticleCell cycle (Georgetown, Tex.)2017
Inhibition of CDK-mediated Smad3 phosphorylation reduces the Pin1-Smad3 interaction and aggressiveness of triple negative breast cancer cells.
Article in Cell cycle (Georgetown, Tex.), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
- Cyclin D1/D2-CDK4 Drives Cell Migration by Orchestrating Cytoskeletal Dynamics Through a TGFβ-FAK-Rac1 Axis.International journal of molecular sciences · 2026Article
- Drugs targeting TGF-β/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.Molecular and cellular biochemistry · 2024Article
- CDK2-activated TRIM32 phosphorylation and nuclear translocation promotes radioresistance in triple-negative breast cancer.Journal of advanced research · 2024Article
- Review
- Small molecule agents for triple negative breast cancer: Current status and future prospects.Translational oncology · 2024Review
- P129, a pyrazole ring-containing isolongifolanone-derivate: synthesis and investigation of anti-glioma action mechanism.Discover oncology · 2024Article
- CDK9 inhibitors in cancer research.RSC medicinal chemistry · 2022Review
- Review
- Role of stromal activin A in human pancreatic cancer and metastasis in mice.Scientific reports · 2021Article
- Cyclin-dependent kinase inhibitors exert distinct effects on patient-derived 2D and 3D glioblastoma cell culture models.Cell death discovery · 2021Article
- A Novel CDK2/9 Inhibitor CYC065 Causes Anaphase Catastrophe and Represses Proliferation, Tumorigenesis, and Metastasis in Aneuploid Cancers.Molecular cancer therapeutics · 2021Article
- Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer.Journal of experimental & clinical cancer research : CR · 2021Article
- Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms.Frontiers in oncology · 2021Review
- Cyclin E overexpression confers resistance to trastuzumab through noncanonical phosphorylation of SMAD3 in HER2+ breast cancer.Cancer biology & therapy · 2020Article
- Pin1 promotes pancreatic cancer progression and metastasis by activation of NF-κB-IL-18 feedback loop.Cell proliferation · 2020Article
- Activin A Modulates Inflammation in Acute Pancreatitis and Strongly Predicts Severe Disease Independent of Body Mass Index.Clinical and translational gastroenterology · 2020Article
- CD155 contributes to the mesenchymal phenotype of triple-negative breast cancer.Cancer science · 2020Article
- Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance.Frontiers in cell and developmental biology · 2020Review
- Function of PIN1 in Cancer Development and Its Inhibitors as Cancer Therapeutics.Frontiers in cell and developmental biology · 2020Review
- Is CDK9 a promising target for both primary and metastatic osteosarcoma?EBioMedicine · 2019Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Triple negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks effective targeted therapies. Although TNBC is not defined by specific therapeutic targets, a subset of patients have tumors that overexpress cyclins. High cyclin D/E expression catalyzes CDK4/2 activity. In turn, CDK4/2 can non-canonically phosphorylate Smad3, a key TGFβ signaling intermediate, and this phosphorylation has been associated with the shift from tumor-suppressive to oncogenic TGFβ pathway action in breast oncogenesis. Additionally, CDK-mediated Smad3 phosphorylation facilitates an interaction between Smad3 and Pin1, a cis-trans isomerase that is also overexpressed in aggressive breast cancers. Treatment with CYC065, a CDK2/9 inhibitor, decreased non-canonical Smad3 phosphorylation and inhibited the Pin1-Smad3 interaction. We hypothesized that the interaction of Pin1 and Smad3, facilitated by CDK-mediated Smad3 phosphorylation, promotes TNBC cell aggressiveness. Inhibition of the Pin1-Smad3 interaction in TNBC cell lines, through depletion of Pin1 or CYC065 treatment, resulted in decreased cell migration/invasion and impeded the EMT program. Inhibition of CDK-mediated phosphorylation of Smad3 by mutagenesis also decreased cell migration, underscoring the importance of non-canonical CDK2 phosphorylation of Smad3 to enable cell motility. Pin1 depletion restored Smad3 protein levels and tumor-suppressive activity, suggesting that the Pin1-Smad3 interaction has a negative impact on canonical Smad3 action. Collectively, the data show that the Pin1-Smad3 interaction, facilitated by CDK-mediated Smad3 phosphorylation, is associated with oncogenic TGFβ signaling and breast cancer progression. Inhibition of this interaction with CYC065 treatment may provide an important therapeutic option for TNBC patients.
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