DAB2IP attenuates chemoresistance of triple‐negative breast cancer through sequestration of RAC1 to prevent β‐catenin nuclear accumulation

Xiong, Zhenchong; Yang, Lin; Li, Ning; Fu, Jianchang; Liu, Peng; Sun, Peng; Wei, Weidong; Xie, Xiaoming

doi:10.1002/ctm2.1133

Cited by 10 publications

(7 citation statements)

References 52 publications

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“…In our study, it presented a higher level in high-risk BC patients, which also hinted at the inferior outcome in this group and was listed as a potential target for BC treatment. DAB2IP belonged to the Ras GTPase-activating protein family and played an anti-tumor role in multiple cancers, such as esophageal squamous cell carcinoma ( 48 ), and triple-negative breast cancer ( 49 ). Additionally, in TBNC, it was shown that the expression of DABI2P was able to alleviate chemoresistance ( 49 ), which means that it was a promising market to improve the prognosis of BC patients.…”

Section: Discussionmentioning

confidence: 99%

“…DAB2IP belonged to the Ras GTPase-activating protein family and played an anti-tumor role in multiple cancers, such as esophageal squamous cell carcinoma ( 48 ), and triple-negative breast cancer ( 49 ). Additionally, in TBNC, it was shown that the expression of DABI2P was able to alleviate chemoresistance ( 49 ), which means that it was a promising market to improve the prognosis of BC patients. HSPA8, a member of the heat shock protein family, participated in protein folding.…”

Section: Discussionmentioning

confidence: 99%

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Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

Yang,

Wang,

Yang

et al. 2024

Front. Immunol.

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BackgroundBreast cancer (BC) is a leading cause of mortality among women, underscoring the urgent need for improved therapeutic predictio. Developing a precise prognostic model is crucial. The role of Endoplasmic Reticulum Stress (ERS) in cancer suggests its potential as a critical factor in BC development and progression, highlighting the importance of precise prognostic models for tailored treatment strategies.MethodsThrough comprehensive analysis of ERS-related gene expression in BC, utilizing both single-cell and bulk sequencing data from varied BC subtypes, we identified eight key ERS-related genes. LASSO regression and machine learning techniques were employed to construct a prognostic model, validated across multiple datasets and compared with existing models for its predictive accuracy.ResultsThe developed ERS-model categorizes BC patients into distinct risk groups with significant differences in clinical prognosis, confirmed by robust ROC, DCA, and KM analyses. The model forecasts survival rates with high precision, revealing distinct immune infiltration patterns and treatment responsiveness between risk groups. Notably, we discovered six druggable targets and validated Methotrexate and Gemcitabine as effective agents for high-risk BC treatment, based on their sensitivity profiles and potential for addressing the lack of active targets in BC.ConclusionOur study advances BC research by establishing a significant link between ERS and BC prognosis at both the molecular and cellular levels. By stratifying patients into risk-defined groups, we unveil disparities in immune cell infiltration and drug response, guiding personalized treatment. The identification of potential drug targets and therapeutic agents opens new avenues for targeted interventions, promising to enhance outcomes for high-risk BC patients and paving the way for personalized cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

Yang,

Wang,

Yang

et al. 2024

Front. Immunol.

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“…DAB2IP is also a negative regulator of the canonical Wnt pathway: by recruiting PP2A phosphatase, it promotes GSK3b activation and β-catenin degradation [ 41 ]; by directly binding Rac1, it prevents β-catenin nuclear transport [ 42 ]. Notably, YAP and TAZ can bind to components of the β-catenin destruction complex and, at least under some circumstances, WNT signaling can lead to YAP/TAZ activation [ 6 , 34 , 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor DAB2IP Is Regulated by Cell Contact and Contributes to YAP/TAZ Inhibition in Confluent Cells

Apollonio,

Bellazzo,

Franco

et al. 2023

Cancers

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External and internal mechanical forces modulate cell morphology, movement, proliferation and metabolism, and represent crucial inputs for tissue homeostasis. The transcriptional regulators YAP and TAZ are important effectors of mechanical signaling and are frequently activated in solid tumors, correlating with metastasis, chemoresistance, and shorter patient survival. YAP/TAZ activity is controlled by various pathways that sense cell shape, polarity, contacts, and mechanical tension. In tumors, aberrant YAP/TAZ activation may result from cancer-related alterations of such regulatory networks. The tumor suppressor DAB2IP is a Ras-GAP and scaffold protein that negatively modulates multiple oncogenic pathways and is frequently downregulated or inactivated in solid tumors. Here, we provide evidence that DAB2IP expression is sustained by cell confluency. We also find that DAB2IP depletion in confluent cells alters their morphology, reducing cell packing while increasing cell stiffness. Finally, we find that DAB2IP depletion in confluent cells favors YAP/TAZ nuclear localization and transcriptional activity, while its ectopic expression in subconfluent cells increases YAP/TAZ retention in the cytoplasm. Together, these data suggest that DAB2IP may function as a sensor of cell interactions, contributing to dampening cellular responses to oncogenic inputs in confluent cells and that DAB2IP loss-of-function would facilitate YAP/TAZ activation in intact epithelia, accelerating oncogenic transformation.

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“…Similarly, DAB2IP loss contributes to docetaxel (DOC) resistance in triple-negative breast cancer (TNBC). Mechanistically, DAB2IP interacts with RAC1 and impedes RAC1-mediated β-catenin nuclear translocation, so that DAB2IP loss promotes the induction of cancer stem cell phenotypes and DOC resistance [35,36].…”

Section: Dab2ip Loss Promotes Resistance To Chemo-and Radio-therapiesmentioning

confidence: 99%

An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications

De Florian Fania,

Bellazzo,

Collavin

2024

Cell Death Differ

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The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors.

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DAB2IP attenuates chemoresistance of triple‐negative breast cancer through sequestration of RAC1 to prevent β‐catenin nuclear accumulation

Cited by 10 publications

References 52 publications

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

Endoplasmic reticulum stress in breast cancer: a predictive model for prognosis and therapy selection

The Tumor Suppressor DAB2IP Is Regulated by Cell Contact and Contributes to YAP/TAZ Inhibition in Confluent Cells

An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications

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