Identification and Validation of a Novel Glycolysis-Related Gene Signature for Predicting the Prognosis and Therapeutic Response in Triple-Negative Breast Cancer

Zheng, Jun; Zhang, Yifan; Han, Guohui; Fan, Mingxia; Du, Min; Zhang, Guochen; Zhang, Bo; Qiao, Jun; Zhang, Sheng‐Xiao; Cao, Ji‐Min

doi:10.1007/s12325-022-02330-y

Cited by 3 publications

(2 citation statements)

References 59 publications

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“…The molecular mechanisms underlying TNBC pathogenesis and progression are not fully understood [3][4][5][6]. A number of studies have suggested that genetic and epigenetic alterations, alterations in signal transduction pathways, and alterations in the tumour microenvironment may play a role in TNBC pathogenesis [3,[7][8][9][10]. Studies have also suggested that tumour-associated macrophages, neutrophils, and other immune cells may contribute to TNBC progression and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Two Targets of Dexmedetomidine in Breast Cancer

Luo

2024

Preprint

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Background: As the most invasive breast cancer (BrCa), triple-negative BrCa (TNBC) has the worst survival. The use of dexmedetomidine potentially affected BrCa surgery and dexmedetomidine was reported to have direct effects on TNBC cells. The objective of this study is to explore the mechanisms underlying the effect of dexmedetomidine on TNBC. Methods: Dexmedetomidine targets were predicted using The Cancer Genome Atlas data SwissTargetPrediction. Cell lines MDA-MB-231, MCF7, and MCF10A were used to validate the targets in TNBC with both clinical samples and cell lines. Cancer cell lines and normal breast cell lines were grouped in cancer and normal groups respectively. Both groups were exposed to dexmedetomidine treatment. Cell Counting Kit-8 was used to determine the effect of dexmedetomidine on cells with target silencing. The binding model of the candidate targets was docked and critical amino acids were mutated to validate the binding model. Results: Dexmedetomidine selectively inhibits cancer cells. Catalytic subunit of the DNA-dependent protein kinase (PRKDC), indoleamine 2,3-dioxygenase 1 (IDO1), opioid receptor kappa 1 (OPRK1), glutaminyl-peptide cyclotransferase (QPCT), macrophage migration inhibitory factor (MIF), potassium voltage-gated channel, subfamily H (Eag-related), member 2 (KCNH2), cholinergic receptor, muscarinic 3 (CHRM3), and potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4 (KCNN4) were identified as dexmedetomidine targets in TNBC. The expression levels of PRKDC, IDO1, MIF, KCNH2, CHRM3, and KCNN4 were found to be upregulated in TNBC tissues compared to non-TNBC tissues(p<0.05). Silencing of these genes was found to reduce the sensitivity of TNBC cells to dexmedetomidine(p<0.05). This effect was counteracted when the silenced genes were overexpressed, resulting in an increase in the sensitivity of cells to dexmedetomidine (p<0.05). Furthermore, a direct interaction between dexmedetomidine and IDO1 and CHRM3 was observed, which regulated the sensitivity of cells to dexmedetomidine(p<0.05).Conclusion: IDO1 and CHRM3 are direct targets of dexmedetomidine in TNBC.

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Section: Introductionmentioning

confidence: 99%

Discovery of Two Targets of Dexmedetomidine in Breast Cancer

Luo

2024

Preprint

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“…Triple-negative breast cancer (TNBC) is highly aggressive and metastatic, resulting in limited treatment options and poor clinical prognosis. − Abnormal tumor metabolism creates a specific tumor microenvironment (TME) that has been closely associated with TNBC metastasis. − Currently, PD-1/PD-L1-based immune checkpoint blockade (ICB) therapy is available to treat diverse cancers, including TNBC. − However, the lack of cytotoxic T lymphocytes (CTLs) and the immunosuppressive character of the TME caused by abnormal tumor metabolism result in a low response rate of TNBC to ICB therapy. − Therefore, an amplified strategy that can complement ICB therapy is urgently needed and should ideally target tumor metabolic regulation to simultaneously activate tumor immunogenicity and reverse the immunosuppressive character of the TME to achieve a long-term antitumor immune response in TNBC.…”

Section: Introductionmentioning

confidence: 99%

Carrier-Free Photodynamic Bioregulators Inhibiting Lactic Acid Efflux Combined with Immune Checkpoint Blockade for Triple-Negative Breast Cancer Immunotherapy

Chen,

Lin,

Mai

et al. 2024

ACS Nano

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Abnormal tumor metabolism creates a complex tumor immune microenvironment that plays a dominant role in the metastasis of triple-negative breast cancer (TNBC). TNBC is insensitive to immune checkpoint blockade (ICB) therapy because of insufficient cytotoxic T lymphocyte (CTL) infiltration and a hyper-lactic acid-suppressive immune microenvironment caused by abnormal glycolysis. Herein, we propose an amplified strategy based on lactic acid regulation to reprogram the immunosuppressive tumor microenvironment (ITM) and combine it with ICB therapy to achieve enhanced antitumor immunotherapy effects. Specifically, we constructed CASN, a carrier-free photodynamic bioregulator, through the self-assembly of the photosensitizer Chlorin e6 and monocarboxylate transporter 1 (MCT1) inhibitor AZD3965. CASN exhibited a uniform structure, good stability, and drug accumulation at the tumor site. CASN-mediated photodynamic therapy following laser irradiation inhibited primary tumor growth and induced immunogenic cell death. Furthermore, CASN reduced lactic acid-mediated regulatory T cell generation and M2 tumor-associated macrophage polarization by blocking MCT1-mediated lactic acid efflux to attenuate immune suppression, inducing the recruitment and activation of CTLs. Ultimately, CASN-mediated immunopotentiation combined with ICB therapy considerably strengthened tumor immunotherapy and effectively inhibited tumor growth and metastasis of TNBC. This synergistic amplification strategy overcomes the limitations of an acidic ITM and presents a potential clinical treatment option for metastatic tumors.

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Targeting ACSS2 activity suspends the formation of chemoresistance through suppressed histone H3 acetylation in human breast cancer

Shui,

Tian,

Zhou

et al. 2024

Preprint

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Histone hyperacetylation is a prevalent occurrence in neoplastic cells within tumors, arising from the coordinated interplay of various biological processes. This phenomenon relies on the robust modulation of gene expression to effectively adapt to environmental adaptations in response to spatial and temporal fluctuations. Histone hyperacetylation has been closely linked to the proliferation, metastasis, and therapeutic resistance of tumor cells. In this investigation, we substantiated the overexpression of the well-documented acetyl-CoA synthetase short-chain family member 2 (ACSS2) at both protein and mRNA levels in breast cancer (BC) cells derived from tumor tissues. Subsequent examinations unveiled that the heightened acetylation of histone H3 in BC cells under environmental stress is contingent upon the accumulation of ACSS2 and enhanced acetyl-CoA synthesis. Intriguingly, the augmentation of H3K9 and H3K27 acetylation (H3K9/K27ac) induced by nutrient stress, mediated by ACSS2, was primarily governed by the histone acetyltransferases (HATs) CBP/p300, with no significant association with conventional histone deacetylases (HDACs). Supplementation with an alternative carbon source, acetate, confirmed that targeted inhibition of ACSS2 mitigated the further elevation of ATP-binding cassette (ABC) transporters, specifically ABC subfamily B member 1 (ABCB1/MDR1) and breast cancer resistance protein (BCRP/ABCG2). These transporters reportedly play crucial roles in both energy metabolic homeostasis and the modulation of intracellular drug concentrations, driven by histone H3 hyperacetylation. Mechanistically, inhibitors of ACSS2 significantly mitigated the resistance of BC cells to doxorubicin and cisplatin, predominantly by reducing H3K27ac levels through the downregulation of nuclear acetyl-CoA content and constraining its binding to the promoters of MDR1 and BCRP. The poor overall survival of BC patients associated with high ACSS2 expression and its positive correlation with MDR1 and BCRP were further confirmed in human BC tumors. Consequently, histone acetylation induced by ACSS2 emerges as a promising epigenetic target for the treatment of BC.

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Identification and Validation of a Novel Glycolysis-Related Gene Signature for Predicting the Prognosis and Therapeutic Response in Triple-Negative Breast Cancer

Cited by 3 publications

References 59 publications

Discovery of Two Targets of Dexmedetomidine in Breast Cancer

Discovery of Two Targets of Dexmedetomidine in Breast Cancer

Carrier-Free Photodynamic Bioregulators Inhibiting Lactic Acid Efflux Combined with Immune Checkpoint Blockade for Triple-Negative Breast Cancer Immunotherapy

Targeting ACSS2 activity suspends the formation of chemoresistance through suppressed histone H3 acetylation in human breast cancer

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