DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

Woditschka, Stephan; Evans, Lynda M.; Duchnowska, Renata; Reed, L. Tiffany; Palmieri, Diane; Qian, Yongzhen; Badve, Sunil; Sledge, George W.; Gril, Brunilde; Aladjem, Mirit I.; Fu, Haiqing; Flores, Natasha; Gökmen–Polar, Yesim; Biernat, Wojciech; Szutowicz-Zielińska, Ewa; Mandat, Tomasz; Trojanowski, Tomasz; Och, Waldemar; Czartoryska-Arłukowicz, Bogumiła; Jassem, Jacek; Mitchell, James B.; Steeg, Patricia S.

doi:10.1093/jnci/dju145

Cited by 57 publications

(49 citation statements)

References 54 publications

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“…The repertoire of alterations was enriched with functional gene networks, with axon guidance, protein kinase A and calcium signalling‐related processes amongst the most significant. While further investigation is required to establish whether these candidates are involved in BM development, it is encouraging that pathways previously implicated in BMs were also identified in this study (eg HER2, GABA‐receptor signalling and DNA double‐strand break repair ).…”

Section: Discussionmentioning

confidence: 78%

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Saunus

Quinn

Patch

et al. 2015

The Journal of Pathology

105

103

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Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome-and RNA-sequencing. The key findings were as follows.

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Section: Discussionmentioning

confidence: 78%

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Saunus

Quinn

Patch

et al. 2015

The Journal of Pathology

105

103

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“…ZDHHC3 ablation not only diminishes in vivo breast tumor growth, but also promotes oxidative stress and senescence. This may explain reduced tumor growth because oxidative stress can diminish tumor growth and/or metastasis (7, 8, 45) and senescence can lead to tumor clearance by immune cells (11, 12, 46). As a key supporter of breast tumor growth, DHHC3 may be a useful cancer target.…”

Section: Discussionmentioning

confidence: 99%

Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence

Sharma

Wang

et al. 2017

Cancer Research

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DHHC-type protein acyltransferases may regulate the localization, stability, and/or activity of their substrates. In this study, we show that the protein palmitoyltransferase DHHC3 is upregulated in malignant and metastatic human breast cancer. Elevated expression of DHHC3 correlated with diminished patient survival in breast cancer and six other human cancer types. ZDHHC3 ablation in human MDA-MB-231 mammary tumor cell xenografts reduced the sizes of both the primary tumor and metastatic lung colonies. Gene array data and fluorescence dye assays documented increased oxidative stress and senescence in ZDHHC3-ablated cells. ZDHHC3-ablated tumors also showed enhanced recruitment of innate immune cells (antitumor macrophages, natural killer cells) associated with clearance of senescent tumors. These antitumor effects were reversed upon reconstitution with wild-type, but not enzyme-active site-deficient DHHC3. Concomitant ablation of the upregulated oxidative stress protein TXNIP substantially negated the effects of ZDHHC3 depletion on oxidative stress and senescence. Diminished DHHC3-dependent palmitoylation of ERGIC3 protein likely played a key role in TXNIP upregulation. In conclusion, DHHC3-mediated protein palmitoylation supports breast tumor growth by modulating cellular oxidative stress and senescence.

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“…Compared with mutant cells, those with reconstituted BRCA1 displayed increased BARD1 expression. BARD1 expression has been observed to facilitate RAD51 overexpression in a TNBC metastatic model to the brain (43). Of note, BRCA1-independent functions of BARD1 have also been reported (44).…”

Section: Discussionmentioning

confidence: 93%

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

Wiegmans

Yap

Ward

et al. 2015

Molecular Cancer Therapeutics

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The triple-negative breast cancer (TNBC) subtype represents a cancer that is highly aggressive with poor patient outcome. Current preclinical success has been gained through synthetic lethality, targeting genome instability with PARP inhibition in breast cancer cells that harbor silencing of the homologous recombination (HR) pathway. Histone deacetylase inhibitors (HDACi) are a class of drugs that mediate epigenetic changes in expression of HR pathway genes. Here, we compare the activity of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA), the class I/IIa HDAC inhibitor valproic acid (VPA), and the HDAC1/2-specific inhibitor romidepsin (ROMI) for their capability to regulate DNA damage repair gene expression and in sensitizing TNBC to PARPi. We found that two of the HDACis tested, SAHA and ROMI, but not VPA, indeed inhibit HR repair and that RAD51, BARD1, and FANCD2 represent key proteins whose inhibition is required for HDACi-mediated therapy with PARP inhibition in TNBC. We also observed that restoration of BRCA1 function stabilizes the genome compared with mutant BRCA1 that results in enhanced polyploid population after combination treatment with HDACi and PARPi. Furthermore, we found that overexpression of the key HR protein RAD51 represents a mechanism for this resistance, promoting aberrant repair and the enhanced polyploidy observed. These findings highlight the key components of HR in guiding synthetic lethality with PARP inhibition and support the rationale for utilizing the novel combination of HDACi and PARPi against TNBC in the clinical setting.

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DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

Abstract: BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species-mediated genotoxic stress in the metastatic brain.

Cited by 57 publications

References 54 publications

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance

Protein Acyltransferase DHHC3 Regulates Breast Tumor Growth, Oxidative Stress, and Senescence

Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

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