Curcumin induces DNA damage by mediating homologous recombination mechanism in triple negative breast cancer

2019 ◽  
Vol 72 (6) ◽  
pp. 1057-1066 ◽  
Author(s):  
Gamze Guney Eskiler ◽  
Elvan Sahin ◽  
Asuman Deveci Ozkan ◽  
Ozlem Tugce Cilingir Kaya ◽  
Suleyman Kaleli
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Recombination Mechanism

scholarly journals CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5782
Author(s):  
Ashwini Makhale ◽  
Devathri Nanayakkara ◽  
Prahlad Raninga ◽  
Kum Kum Khanna ◽  
Murugan Kalimutho
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Triple Negative ◽  
Annexin V ◽  
Replication Stress ◽  
Breast Cancer Cell Lines ◽  
Combination Strategy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

scholarly journals Combined homologous recombination repair deficiency and immune activation analysis for predicting intensified responses of anthracycline, cyclophosphamide and taxane chemotherapy in triple-negative breast cancer

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Gaoming Liao ◽  
Zedong Jiang ◽  
Yiran Yang ◽  
Cong Zhang ◽  
Meiting Jiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Immune Activation ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Homologous Recombination Repair ◽  
Repair Deficiency ◽  
Recombination Repair

Abstract Background Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. Methods Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. Results HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). Conclusions These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

Rad51 Silencing with siRNA Delivered by Porous Silicon-Based Microparticle Enhances the Anti-Cancer Effect of Doxorubicin in Triple-Negative Breast Cancer

2021 ◽  
Vol 17 (12) ◽  
pp. 2351-2363
Author(s):  
Zeliang Wu ◽  
Lin Zhu ◽  
Junhua Mai ◽  
Haifa Shen ◽  
Rong Xu
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Porous Silicon ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Due to its high heterogeneity and aggressiveness, cytotoxic chemotherapy is still a mainstay treatment for triple negative breast cancer. Unfortunately, the above mentioned has not significantly ameliorated TNBC patients and induces drug resistance. Exploring the mechanisms underlying the chemotherapy sensitivity of TNBC and developing novel sensitization strategies are promising approaches for improving the prognosis of patients. Rad51, a key regulator of DNA damage response pathway, repairs DNA damage caused by genotoxic agents through “homologous recombination repair.” Therefore, Rad51 inhibition may increase TNBC cell sensitivity to anticancer agents. Based on these findings, we first designed Rad51 siRNA to inhibit the Rad51 protein expression in vitro and evaluated the sensitivity of TNBC cells to doxorubicin. Subsequently, we constructed discoidal porous silicon microparticles (pSi) and encapsulated discoidal 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes/siRad51 (PS-DOPC/siRad51) to explore the synergistic antitumor effects of siRad51 and doxorubicin on two mouse models of TNBC in vivo. Our in vitro studies indicated that siRad51 enhanced the efficacy of DOX chemotherapy and significantly suppressed TNBC cell proliferation and metastasis. This effect was related to apoptosis induction and epithelial to mesenchymal transition (EMT) inhibition. siRad51 altered the expression of apoptosis- and EMT-related proteins. In orthotopic and lung metastasis xenograft models, the administration of PS-DOPC/siRad51 in combination with DOX significantly alleviated the primary tumor burden and lung metastasis, respectively. Our current studies present an efficient strategy to surmount chemotherapy resistance in TNBC through microvector delivery of siRad51.

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