<i>BRCA1</i> Promoter Methylation Is Linked to Defective Homologous Recombination Repair and Elevated <i>miR-155</i> to Disrupt Myeloid Differentiation in Myeloid Malignancies

Poh, Weijie; Dilley, Robert L.; Moliterno, Alison R.; Maciejewski, Jaroslaw P.; Pratz, Keith W.; McDevitt, Michael A.; Herman, James G.

doi:10.1158/1078-0432.ccr-18-0179

Cited by 15 publications

(14 citation statements)

References 51 publications

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“…Loss of BRCA activity can occur by somatic or germline mutation, loss of heterozygosity, copy number alterations (regional or whole chromosome alterations or deletions), or promoter methylation with gene silencing [59,60]. Multiple investigators have demonstrated that BRCA gene silencing via hypermethylation occurs not only in AML but also in multiple solid tumors, including breast, ovary, and prostate cancer [56,57,[59][60][61][62][63][64]. In addition, hypermethylation has been reported as a consequence of both cytotoxic chemotherapy and radiation [58].…”

Section: Hrd and T-mds/amlmentioning

confidence: 99%

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

2020

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In this review we summarize the impact of the various modalities of breast cancer therapy coupled with intrinsic patient factors on incidence of subsequent treatmentinduced myelodysplasia and acute myelogenous leukemia (t-MDS/AML). It is clear that risk is increased for patients treated with radiation and chemotherapy at younger ages. Radiation is associated with modest risk, whereas chemotherapy, particularly the combination of an alkylating agent and an anthracycline, carries higher risk and radiation and chemotherapy combined increase the risk markedly. Recently, treatment with granulocyte colony-stimulating factor (G-CSF), but not pegylated G-CSF, has been identified as a factor associated with increased t-MDS/AML risk. Two newly identified associations may link homologous DNA repair gene deficiency and poly (ADP-ribose) polymerase inhibitor treatment to increased t-MDS/AML risk. When predisposing factors, such as young age, are combined with an increasing number of potentially leukemogenic treatments that may not confer large risk singly, the risk of t-MDS/AML appears to increase. Patient and treatment factors combine to form a biological cascade that can trigger a myelodysplastic event. Patients with breast cancer are often exposed to many of these risk factors in the course of their treatment, and triple-negative patients, who are often younger and/or BRCA positive, are often exposed to all of them. It is important going forward to identify effective therapies without these adverse associated effects and choose existing therapies that minimize the risk of t-MDS/ AML without sacrificing therapeutic gain. The Oncologist 2020;25:391-397 Implications for Practice: Breast cancer is far more curable than in the past but requires multimodality treatment. Great care must be taken to use the least leukemogenic treatment programs that do not sacrifice efficacy. Elimination of radiation and anthracycline/alkylating agent regimens will be helpful where possible, particularly in younger patients and possibly those with homologous repair deficiency (HRD). Use of colony-stimulating factors should be limited to those who truly require them for safe chemotherapy administration. Further study of a possible leukemogenic association with HRD and the various forms of colony-stimulating factors is badly needed.

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Section: Hrd and T-mds/amlmentioning

confidence: 99%

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

2020

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“…Here, we presented HAI-1 promoter hypomethylation in a proportion of HCC patients and linked expression upregulation. Built upon the several published whole-genome bisulfite analysis studies which described that methylation alterations play a role in inhibiting differentiation in hematopoietic malignancies [44, 45], we did observe that this epigenetic change in HAI-1 contributes reduced differentiation ability in this retrospective HCC case cohort. While data in the current study provided some evidence, the association between the promoter methylation level of HAI-1 and HCC differentiation status needs to be further confirmed in a larger patient cohort.…”

Section: Discussionmentioning

confidence: 51%

Promoter Hypomethylation Is Responsible for Upregulated Expression of HAI-1 in Hepatocellular Carcinoma

Rahman

et al. 2019

Disease Markers

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An upregulated expression of hepatocyte growth factor activator inhibitor type 1 (HAI-1) in hepatocellular carcinomas (HCC) associates with poor prognosis, but the underlying mechanism for expression regulation has not been elucidated. HAI-1 was expressed in HCC cell line Hep3B cells at a high level but absent or has a low level in other HCC cell lines HepG2 and SMMC7721 and immortal normal liver cell line L02 at transcriptional and translational levels, respectively. A dual-luciferase reporter assay showed that transcriptional activity of HAI-1 in the promoter region (-452 bp to -280 bp from the mRNA start site) was strongly enhanced in Hep3B and SMMC7721. Bisulfite genomic sequencing results of the HAI-1 promoter region showed an inverse correlation between levels of promoter methylation and expression in HCC cells. The expression level of HAI-1 in SMMC7721, HepG2, and L02 cells was elevated after 5-Aza-2′-deoxycytidine treatment. Hypomethylation of the HAI-1 promoter region contributed to the elevated HAI-1 expression in HCC tissues. In addition, the hypomethylation of the HAI-1 promoter region correlated with poor differentiation status of HCC tissues. Our findings indicate that promoter hypomethylation is an important mechanism for aberrant HAI-1 expression regulation in HCC.

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“…Previous studies have shown a close link between low expression of BRCA1 and its promoter methylation. 20 Previous studies showed that BRCA1 promoter methylation was observed in about 20%–60% of TNBC patients. 8,21,22 The methylation status of BRCA1 is significantly correlated with the co-expression of DNMTs.…”

Section: Resultsmentioning

confidence: 99%

“…Low expression of BRCA1 is closely related to its promoter methylation. 20 Flavonoids can affect DNA methylation and genome stability. 33,34 Moreover, DNMT can affect the expression of BRCA1.…”

Section: Discussionmentioning

confidence: 99%

Liquiritigenin decreases tumorigenesis by inhibiting DNMT activity and increasing BRCA1 transcriptional activity in triple-negative breast cancer

Liang

Zhang

Gao

et al. 2020

Exp Biol Med (Maywood)

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As a selective estrogen receptor β agonist, the natural flavonoid liquiritigenin reportedly inhibits invasiveness of breast cancer cells, but its specific role and mechanism remain largely unclear. In this study, cells from the triple negative breast cancer lines MDA-MB-231 and BT549 were incubated with different concentrations of liquiritigenin. The results indicated that low concentrations had no significant cytotoxic effect, whereas high concentrations decreased viability of both MDA-MB-231 and BT549 cells. Liquiritigenin treatment also resulted in increased apoptosis and enhanced Caspase3 activity. After liquiritigenin treatment, we observed decreased invasive and migratory capacities of cells, as well as upregulated E-cadherin and downregulated N-cadherin, vimentin, and MMP9. Interestingly, liquiritigenin increased the mRNA and protein expression of breast cancer 1 (BRCA1). It also increased p21 and growth arrest and DNA-damage-inducible 45 alpha (GADD45A) levels, accompanied by decreased cellular DNA methyltransferase (DNMT) activity and downregulation of DNMT1, DNMT3a, and DNMT3b. These findings suggest that liquiritigenin can inhibit malignant behavior of triple negative breast cancer cells by inhibiting DNMT activity and increasing BRCA1 expression and its transcriptional activity. Liquiritigenin thus may be a promising candidate for the treatment of breast cancer. Impact statement Triple negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis and higher metastatic rates and relapse frequencies than other breast cancers. Natural flavonoid liquiritigenin reportedly inhibits invasiveness of TNBC MDA-MB-231 cells, but its specific role and mechanism remain unclear. This study administered different doses of liquiritigenin into TNBC cell lines MDA-MB-231 and BT549, and found that it hindered cell proliferation, increased apoptosis, and repressed cell invasion and migration. BRCA1 exerts multiple functions and is closely related to the occurrence and development of breast cancer. Interestingly, the mRNA and protein expression of BRCA1 increased after liquiritigenin administration. Liquiritigenin also upregulated two downstream genes of BRCA1 (p21 and DNA-damage-inducible 45 alpha), decreased cellular DNA methyltransferase (DNMT) activity, and reduced BRCA1 promoter methylation. Thus, liquiritigenin may be a promising candidate for the treatment of TNBC due to its inhibition of DNMT activity and upregulation of BRCA1.

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BRCA1 Promoter Methylation Is Linked to Defective Homologous Recombination Repair and Elevated miR-155 to Disrupt Myeloid Differentiation in Myeloid Malignancies

Cited by 15 publications

References 51 publications

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

Promoter Hypomethylation Is Responsible for Upregulated Expression of HAI-1 in Hepatocellular Carcinoma

Liquiritigenin decreases tumorigenesis by inhibiting DNMT activity and increasing BRCA1 transcriptional activity in triple-negative breast cancer

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