scholarly journals Chemotherapy of HER2- and MDM2-Enriched Breast Cancer Subtypes Induces Homologous Recombination DNA Repair and Chemoresistance

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4501
Author(s):  
Marcin Herok ◽  
Bartosz Wawrzynow ◽  
Marta J. Maluszek ◽  
Maciej B. Olszewski ◽  
Alicja Zylicz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Cell Line ◽  
Parp Inhibitor ◽  
Proliferation Assay ◽  
Cancer Subtypes ◽  
Cancer Subtype ◽  
Mdm2 Expression

Analyzing the TCGA breast cancer database, we discovered that patients with the HER2 cancer subtype and overexpression of MDM2 exhibited decreased post-treatment survival. Inhibition of MDM2 expression in the SKBR3 cell line (HER2 subtype) diminished the survival of cancer cells treated with doxorubicin, etoposide, and camptothecin. Moreover, we demonstrated that inhibition of MDM2 expression diminished DNA repair by homologous recombination (HR) and sensitized SKBR3 cells to a PARP inhibitor, olaparib. In H1299 (TP53−/−) cells treated with neocarzinostatin (NCS), overexpression of MDM2 WT or E3-dead MDM2 C478S variant stimulated the NCS-dependent phosphorylation of ATM, NBN, and BRCA1, proteins involved in HR DNA repair. However, overexpression of chaperone-dead MDM2 K454A variant diminished phosphorylation of these proteins as well as the HR DNA repair. Moreover, we demonstrated that, upon NCS treatment, MDM2 K454A interacted with NBN more efficiently than MDM2 WT and that MDM2 WT was degraded more efficiently than MDM2 K454A. Using a proliferation assay, we showed that overexpression of MDM2 WT, but not MDM2 K454A, led to acquisition of resistance to NCS. The presented results indicate that, following chemotherapy, MDM2 WT was released from MDM2-NBN complex and efficiently degraded, hence allowing extensive HR DNA repair leading to the acquisition of chemoresistance by cancer cells.

scholarly journals Survivin contributes to DNA repair by homologous recombination in breast cancer cells

2015 ◽  
Vol 155 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Eloïse Véquaud ◽  
Grégoire Desplanques ◽  
Pascal Jézéquel ◽  
Philippe Juin ◽  
Sophie Barillé-Nion
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Breast Cancer Cells

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals DNA Repair by Homologous Recombination, But Not by Nonhomologous End Joining, Is Elevated in Breast Cancer Cells

Neoplasia ◽  
2009 ◽  
Vol 11 (7) ◽  
pp. 683-IN3 ◽  
Author(s):  
Zhiyong Mao ◽  
Ying Jiang ◽  
Xiang Liu ◽  
Andrei Seluanov ◽  
Vera Gorbunova
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Nonhomologous End Joining ◽  
End Joining

scholarly journals Mammary lineage dictates homologous recombination repair and PARP inhibitor vulnerability

2021 ◽  
Author(s):  
Hyeyeon Kim ◽  
Alison E Casey ◽  
Luis Palomero ◽  
Mathepan Mahendralingam ◽  
Michael Parsons ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Cell Types ◽  
Mammary Epithelial ◽  
Dna Double Strand Breaks ◽  
Dsb Repair ◽  
Cancer Subtypes ◽  
New Strategy ◽  
Non Homologous End Joining

It has long been assumed that all normal cells have the same capacity to engage homologous recombination (HR) and non-homologous end joining (NHEJ) to repair DNA double-strand breaks (DSBs), a concept exploited for DNA-damaging chemotherapeutics. We show that mammary epithelial lineage dictates the DSB repair pathway choice. Primary mammary proteomes and DSB repair enumeration by γ-H2AX, Rad51 and DNA-PKc foci reveal that NHEJ operates in all epithelial cells, but high-fidelity HR is restricted to the luminal lineage. This translates to divergent poly (ADP-ribose) polymerase inhibitor (PARPi) vulnerability of mammary epithelial progenitor activity in both mouse and human, irrespective of the BRCA1/2 status. Proteome-defined lineage-specific signatures correlate to breast cancer subtypes and predict PARPi response of triple-negative human breast cancer xenografts. These intrinsically divergent HR characteristics of mammary cell types underpin a new strategy for identifying PARPi responders.

scholarly journals Inhibition of DNA Repair Pathways and Induction of ROS Are Potential Mechanisms of Action of the Small Molecule Inhibitor BOLD-100 in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2647
Author(s):  
Suzanne Bakewell ◽  
Isabel Conde ◽  
Yassi Fallah ◽  
Mathew McCoy ◽  
Lu Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Parp Inhibitor ◽  
Maximum Tolerated Dose ◽  
Repair Pathway

BOLD-100, a ruthenium-based complex, sodium trans-[tetrachloridobis (1H-indazole) ruthenate (III)] (also known as IT-139, NKP1339 or KP1339), is a novel small molecule drug that demonstrated a manageable safety profile at the maximum tolerated dose and modest antitumor activity in a phase I clinical trial. BOLD-100 has been reported to inhibit the upregulation of the endoplasmic reticulum stress sensing protein GRP78. However, response to BOLD-100 varies in different cancer models and the precise mechanism of action in high-response versus low-response cancer cells remains unclear. In vitro studies have indicated that BOLD-100 induces cytostatic rather than cytotoxic effects as a monotherapy. To understand BOLD-100-mediated signaling mechanism in breast cancer cells, we used estrogen receptor positive (ER+) MCF7 breast cancer cells to obtain gene-metabolite integrated models. At 100 μM, BOLD-100 significantly reduced cell proliferation and expression of genes involved in the DNA repair pathway. BOLD-100 also induced reactive oxygen species (ROS) and phosphorylation of histone H2AX, gamma-H2AX (Ser139), suggesting disruption of proper DNA surveillance. In estrogen receptor negative (ER−) breast cancer cells, combination of BOLD-100 with a PARP inhibitor, olaparib, induced significant inhibition of cell growth and xenografts and increased gamma-H2AX. Thus, BOLD-100 is a novel DNA repair pathway targeting agent and can be used with other chemotherapies in ER− breast cancer.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

The Impact of Antioxidants from the Diet on Breast Cancer Cells Monitored by Raman Microspectroscopy

2018 ◽  
Vol 16 (2) ◽  
pp. 127-137
Author(s):  
Paula Sofia Coutinho Medeiros ◽  
Ana Lúcia Marques Batista de Carvalho ◽  
Cristina Ruano ◽  
Juan Carlos Otero ◽  
Maria Paula Matos Marques
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Breast Adenocarcinoma ◽  
Coumaric Acid ◽  
Human Breast ◽  
The Impact

Background: The impact of the ubiquitous dietary phenolic compound p-coumaric acid on human breast cancer cells was assessed, through a multidisciplinary approach: Combined biological assays for cytotoxicity evaluation and biochemical profiling by Raman microspectroscopic analysis in cells. </P><P> Methods: Para-coumaric acid was shown to exert in vitro chemoprotective and antitumor activities, depending on the concentration and cell line probed: a significant anti-invasive ability was detected for the triple-negative MDA-MB-231 cells, while a high pro-oxidant effect was found for the estrogen- dependent MCF-7 cells. A striking cell selectivity was obtained, with a more noticeable outcome on the triple-negative MDA-MB-231 cell line. Results: The main impact on the cellular biochemical profile was verified to be on proteins and lipids, thus justifying the compound´s anti-invasive effect and chemoprotective ability. Conclusion: p-Coumaric acid was thus shown to be a promising chemoprotective/chemotherapeutic agent, particularly against the low prognosis triple-negative human breast adenocarcinoma.

Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes

2019 ◽  
Vol 18 (15) ◽  
pp. 2156-2168 ◽  
Author(s):  
Magda F. Mohamed ◽  
Nada S. Ibrahim ◽  
Ahmed H.M. Elwahy ◽  
Ismail A. Abdelhamid
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Cell Line ◽  
Lung Carcinoma ◽  
Carcinoma Cell ◽  
Normal Cells ◽  
Lung Carcinoma Cell Line ◽  
Molecular Studies ◽  
Dihydropyridine Derivatives

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

Continuous Hypoxia and Glucose Metabolism, The Effects on Genes Expression in Mcf7 Breast Cancer Cell Line

2020 ◽  
Vol 20 ◽  
Author(s):  
Abdel Qader Al Bawab ◽  
Malek Zihlif ◽  
Yazan Jarrar ◽  
Ahmad Saleh
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Cell Line ◽  
Breast Cancer Cell Line ◽  
Warburg Effect ◽  
Cancer Cell Line ◽  
Mcf7 Cells ◽  
Genetic Changes ◽  
Genes Expression

Background: Hypoxia (deprived oxygen in tissues) may induce molecular and genetic changes in cancer cells. Objective: Investigating the genetic changes of glucose metabolism in breast cancer cell line (MCF7) after exposure to continuous hypoxia (10 and 20 cycles exposure of 72 hours continuously on a weekly basis). Method: Gene expression of MCF7 cells was evaluated using real-time polymerase chain reaction- array method. Furthermore, cell migration and wound healing assays were also applied. Results: It was found that 10 episodes of continuous hypoxia activated Warburg effect in MCF7 cells via the significant up-regulation of genes involved in glycolysis (ANOVA, p value < 0.05). The molecular changes were associated with the ability of MCF7 cells to divide and migrate. Interestingly, after 20 episodes of continuous hypoxia, the expression glycolysis mediated genes has dropped significantly (from 30 to 9 folds). This could be attributed to the adaptive ability of cancer cells. Conclusion: It is concluded that 10 hypoxic episodes increased the survival rate and the aggressiveness of MCF7 cells and induced Warburg effect by up-regulation of the glycolysis mediating genes expression.

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