Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer

Fernández-Cabezudo, Maria J.; Faour, Issam; Jones, Kenneth L.; Champagne, Devin P.; Jaloudi, Mohammed; Mohamed, Yassir A.; Bashir, Ghada; Almarzooqi, Saeeda; Albawardi, Alia; Hashim, M. Jawad; Roberts, Thomas S.; El-Salhat, Haytham; El-Taji, Hakam; Kassis, Adnan; O’Sullivan, Dylan E.; Christensen, Brock C.; DeGregori, James; al-Ramadi, Basel K.; Rincón, Mercedes

doi:10.1172/jci.insight.86873

Cited by 18 publications

(31 citation statements)

References 49 publications

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“…A locus containing RAD51C has been associated with TGCT susceptibility ( Chung et al, 2013 ), highlighting the potential importance of homologous repair deficiency in TGCTs. We also found epigenetic silencing in DNAJC15/MCJ ( Figure S4H ), which in breast and uterine cancer cells has been associated with drug resistance ( Fernández-Cabezudo et al, 2016 ).…”

Section: Resultsmentioning

confidence: 70%

“…BRCA1 and RAD51C promoter methylation in 35% of non-EC NSGCTs makes a significant proportion of these tumors candidates for treatment with PARP inhibitors ( Cavallo et al, 2012 ). Finally, recurrent epigenetic silencing of DNAJC15/MCJ in NGSCTs makes these genes candidate predictive markers, because their expression in breast and uterine cancer cells is reportedly associated with drug resistance ( Fernández-Cabezudo et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

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Integrated Molecular Characterization of Testicular Germ Cell Tumors

Shen¹,

Shih²,

Hollern³

et al. 2018

Cell Reports

364

426

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SUMMARYWe studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance—KIT, KRAS, and NRAS—exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.

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Section: Resultsmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Shen¹,

Shih²,

Hollern³

et al. 2018

Cell Reports

364

426

View full text Add to dashboard Cite

show abstract

“…Notable genes include: ZFP82 , which is epigenetically silenced and suspected to function as a tumor suppressor (Xiao et al, 2014) (Yu et al, 2015) (Fan et al, 2016); PARP6 hypermethylation (Honda et al, 2016) (Qi et al, 2016); DNAJC15, which is hypermethylated in a number of tumor types (Ehrlich et al, 2002; Lindsey et al, 2006), and whose inactivation has been associated with chemotherapeutic drug resistance in breast (Fernandez-Cabezudo et al, 2016) and ovarian cancers (Rein et al, 2011). We also identified genes that were epigenetically silenced at low prevalence through manual examination of the genes known to be important in cancer, including BRCA1 and MGMT (each silenced in one case).…”

Section: Resultsmentioning

confidence: 99%

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Raphael¹,

Hruban²,

Aguirre³

et al. 2017

Cancer Cell

1,480

1,072

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SUMMARY We performed integrated genomic, transcriptomic and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1 and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1 and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

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“…The characteristics that define successful cancerous tumors include not only the capacity for continuous, self-sufficient proliferation but also increased resistance to apoptosis, acquisition of migration and invasion capabilities, and pro-angiogenic potential ( 45 ). Human TNBC represent a major challenge in treatment owing to their inherent resistance to chemotherapy and high capacity for metastatic spread ( 46 , 47 ). The objective of this study was to investigate the influence of MH on the growth of two distinct human breast cancer cell lines, the TNBC MDA-MB-231 cells and ER-positive MCF-7 cells, and characterize the earliest molecular targets involved.…”

Section: Discussionmentioning

confidence: 99%

The IL-6/STAT3 Signaling Pathway Is an Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells

et al. 2017

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There is renewed interest in the potential use of natural compounds in cancer therapy. Previously, we demonstrated the anti-tumor properties of manuka honey (MH) against several cancers. However, the underlying mechanism and molecular targets of this activity remain unknown. For this study, the early targets of MH and its modulatory effects on proliferation, invasiveness, and angiogenic potential were investigated using two human breast cancer cell lines, the triple-negative MDA-MB-231 cells and estrogen receptor-positive MCF-7 cells, and the non-neoplastic breast epithelial MCF-10A cell line. Exposure to MH at concentrations of 0.3–1.25% (w/v) induced a dose-dependent inhibition of the proliferation of MDA-MB-231 and MCF-7, but not MCF-10A, cells. This inhibition was independent of the sugar content of MH as a solution containing equivalent concentrations of its three major sugars failed to inhibit cell proliferation. At higher concentrations (>2.5%), MH was found to be generally deleterious to the growth of all three cell lines. MH induced apoptosis of MDA-MB-231 cells through activation of caspases 8, 9, 6, and 3/7 and this correlated with a loss of Bcl-2 and increased Bax protein expression in MH-treated cells. Incubation with MH induced a time-dependent translocation of cytochrome c from mitochondria to the cytosol and Bax translocation from the cytosol into the mitochondria. MH also induced apoptosis of MCF-7 cells via the activation of caspases 9 and 6. Low concentrations of MH (0.03–1.25% w/v) induced a rapid reduction in tyrosine-phosphorylated STAT3 (pY-STAT3) in MDA-MB-231 and MCF-7 cells. Maximum inhibition of pY-STAT3 was observed at 1 h with a loss of >80% and coincided with decreased interleukin-6 (IL-6) production. Moreover, MH inhibited the migration and invasion of MDA-MB-231 cells as well as the angiogenic capacity of human umbilical vein endothelial cells. Our findings identify multiple functional pathways affected by MH in human breast cancer and highlight the IL-6/STAT3 signaling pathway as one of the earliest potential targets in this process.

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Deficiency of mitochondrial modulator MCJ promotes chemoresistance in breast cancer

Cited by 18 publications

References 49 publications

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

The IL-6/STAT3 Signaling Pathway Is an Early Target of Manuka Honey-Induced Suppression of Human Breast Cancer Cells

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