Functional profiling of nucleotide Excision repair in breast cancer

Rajkumar-Calkins, Anne; Szalat, Raphaël; Dreze, Matija; Khan, Iman; Frazier, Zoë; Reznichenkov, Elizaveta; Schnorenberg, Mathew R.; Tsai, Yi‐Fang; Nguyen, Huy; Kochupurakkal, Bose; D’Andrea, Alan D.; Shapiro, Geoffrey I.; Lazaro, Jean-Bernard; Mouw, Kent W.

doi:10.1016/j.dnarep.2019.102697

Cited by 13 publications

(18 citation statements)

References 34 publications

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“…Expression levels of XPF have been used to functionally characterize NER in breast cancer cell lines and patient samples. 35 NER deficiency was associated with epigenetic silencing of XPF (ERCC4) and decreased expression of this NER nuclease, which is consistent with the results shown for HCC1806 and MDA-468 cells ( Figure 2C and D). However, the NER defect in MDA-231 cells did not show these expression changes (Figure 2).…”

Section: Discussionsupporting

confidence: 90%

“…ERCC1 and XPF have been suggested as biomarkers for therapeutic responses to crosslinking agents like cisplatin or irinotecan, but specific inhibitors for NER proteins are still being developed. 35 – 37 One recent report used RNAi and spironolactone to inhibit XPB to induce sensitivity to alkylating agents and overcome alkylating agent resistance in multiple myeloma. 38 Triptolide also inhibits the ATPase activity of XPB and has been shown to sensitize breast cancer cell lines to doxorubicin and cisplatin.…”

Section: Discussionmentioning

confidence: 99%

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Exploiting DNA repair defects in triple negative breast cancer to improve cell killing

et al. 2020

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Background: The lack of molecular targets for triple negative breast cancer (TNBC) has limited treatment options and reduced survivorship. Identifying new molecular targets may help improve patient survival and decrease recurrence and metastasis. As DNA repair defects are prevalent in breast cancer, we evaluated the expression and repair capacities of DNA repair proteins in preclinical models. Methods: DNA repair capacity was analyzed in four TNBC cell lines, MDA-MB-157 (MDA-157), MDA-MB-231 (MDA-231), MDA-MB-468 (MDA-468), and HCC1806, using fluorescence multiplex host cell reactivation (FM-HCR) assays. Expression of DNA repair genes was analyzed with RNA-seq, and protein expression was evaluated with immunoblot. Responses to the combination of DNA damage response inhibitors and primary chemotherapy drugs doxorubicin or carboplatin were evaluated in the cell lines. Results: Defects in base excision and nucleotide excision repair were observed in preclinical TNBC models. Gene expression analysis showed a limited correlation between these defects. Loss in protein expression was a better indicator of these DNA repair defects. Over-expression of PARP1, XRCC1, RPA, DDB1, and ERCC1 was observed in TNBC preclinical models, and likely contributed to altered sensitivity to chemotherapy and DNA damage response (DDR) inhibitors. Improved cell killing was achieved when primary therapy was combined with DDR inhibitors for ATM, ATR, or CHK1. Conclusion: Base excision and nucleotide excision repair pathways may offer new molecular targets for TNBC. The functional status of DNA repair pathways should be considered when evaluating new therapies and may improve the targeting for primary and combination therapies with DDR inhibitors.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Exploiting DNA repair defects in triple negative breast cancer to improve cell killing

et al. 2020

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“…This explains the detected [ 125 I]-PARPi-01 sensitivity in BT20 [ 29 ]. Similarly, MDA-MB-468 have a heavy deficiency of NER pathway that possibly contributes additionally to the PARPi sensitivity [ 13 , 49 ]. However, the therapeutic effect can be attributed mainly to their underlying lack of DNA repair to rescue Auger emitter induced DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

Sankaranarayanan

Peil

Vogg

et al. 2022

Cancers

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PARP1 inhibitors (PARPi) are currently approved for BRCAmut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [125I] coupled olaparib derivative: [125I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCAwt/mut). Anchorage independent growth potential was evaluated using soft agar assay. [125I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [125I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCAwt cell lines. The clonogenic survival was significantly reduced after treatment with [125I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [125I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

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“…They can translate each other and participate in the tricarboxylic acid (TCA) cycle, the dysbiosis of which is associated with the pathogenesis and development of tumors [ 51 ]. Additionally, the decreased pathways in nucleotide excision repair (NER) and endocytosis in brain tumors insinuate a disruption in epigenetics and cellular processes [ 52 , 53 ]. NER is a key DNA repair mechanism that can remove helices distorting DNA adducts.…”

Section: Discussionmentioning

confidence: 99%

The role of gut microbiota in patients with benign and malignant brain tumors: a pilot study

et al. 2022

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Gut microbiota is associated with the growth of various tumors, including malignant gliomas, through the brain-gut axis. Moreover, the gut microbiota in patients with malignant tumors may considerably differ from those with benign tumors. However, the associations of gut microbiota with benign and malignant brain tumors remain unclear. Hence, in order to explore these underlying relationships, patients with benign meningioma (n = 32), malignant glioma (n = 27), and healthy individuals (n = 41) were selected to participate in this study. The results showed that the diversity of the microbial ecosystem in brain tumor patients were less than the healthy controls, while no significant differences were observed between the meningioma and glioma groups. The microbial composition also differed significantly between individuals with brain tumors and healthy participants. In meningioma group, pathogenic bacteria like Enterobacteriaceae were increased , whereas certain carcinogenic bacteria were overrepresented in the glioma group, including Fusobacterium and Akkermansia . Furthermore, benign and malignant brain tumor patients lacked SCFA-producing probiotics. Thus , a microbial biomarker panel including Fusobacterium, Akkermansia, Escherichia/Shigella, Lachnospira, Agathobacter , and Bifidobacterium was established. Diagnostic models confirmed that this panel could distinguish between brain tumor patients and healthy patients. Additionally, gut microbiota can affect the differentiation and proliferation of brain tumors via several metabolic pathways based on annotations from the Kyoto Encyclopedia of Genes and Genomes (KEGG). This is the first study designed to investigate whether gut microbiota differs between benign and malignant brain tumor patients, and our work concluded that intestinal flora is a valuable tool for the diagnosis and treatment of brain tumors.

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Functional profiling of nucleotide Excision repair in breast cancer

Cited by 13 publications

References 34 publications

Exploiting DNA repair defects in triple negative breast cancer to improve cell killing

Exploiting DNA repair defects in triple negative breast cancer to improve cell killing

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study

The role of gut microbiota in patients with benign and malignant brain tumors: a pilot study

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