Abstract 2213: Investigation of treatment resistance with DNA-damage agents in patients with triple negative breast cancer by ctDNA

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.

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Quantitative phosphoproteomics reveals genistein as a modulator of cell cycle and DNA damage response pathways in triple-negative breast cancer cells

International Journal of Oncology ◽

10.3892/ijo.2016.3327 ◽

2016 ◽

Vol 48 (3) ◽

pp. 1016-1028 ◽

Cited By ~ 25

Author(s):

YI FANG ◽

QIAN ZHANG ◽

XIN WANG ◽

XUE YANG ◽

XIANGYU WANG ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Dna Damage ◽

Cancer Cells ◽

Dna Damage Response ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Damage Response ◽

Quantitative Phosphoproteomics

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Predictive significance of DNA damage and repair biomarkers in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: An exploratory analysis

Oncotarget ◽

10.18632/oncotarget.6001 ◽

2015 ◽

Vol 6 (40) ◽

pp. 42773-42780 ◽

Cited By ~ 11

Author(s):

Patrizia Vici ◽

Anna Di Benedetto ◽

Cristiana Ercolani ◽

Laura Pizzuti ◽

Luigi Di Lauro ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Neoadjuvant Chemotherapy ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Exploratory Analysis ◽

Breast Cancer Patients ◽

Dna Damage And Repair

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Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

Cancer Research Communications ◽

10.1158/2767-9764.crc-21-0099 ◽

2021 ◽

Vol 1 (3) ◽

pp. 140-147

Author(s):

Cynthia Villarreal-Garza ◽

Ana S. Ferrigno ◽

Alejandro Aranda-Gutierrez ◽

Paul H. Frankel ◽

Nora H. Ruel ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Point Mutations ◽

Treatment Resistance ◽

Cancer Center ◽

Breast Cancers ◽

Entire Cohort ◽

Pathogenic Variants ◽

Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

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Bisnaphthalimidopropyl diaminodicyclohexylmethane induces DNA damage and repair instability in triple negative breast cancer cells via p21 expression

Chemico-Biological Interactions ◽

10.1016/j.cbi.2015.10.017 ◽

2015 ◽

Vol 242 ◽

pp. 307-315 ◽

Cited By ~ 6

Author(s):

Gemma A. Barron ◽

Marie Goua ◽

Isao Kuraoka ◽

Giovanna Bermano ◽

Shigenori Iwai ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Dna Damage And Repair

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

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3198 ◽

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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