DNA Methyltransferase Gene Polymorphisms for Prediction of Radiation-Induced Skin Fibrosis after Treatment of Breast Cancer: A Multifactorial Genetic Approach

Abstract Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients’ self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR = 0.45, 95% CI: 0.25–0.82, P = 0.01) and functional interference (OR = 0.48, 95% CI: 0.24–0.95, P = 0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.

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Impact of Pharmaceutical Prophylaxis on Radiation-Induced Liver Disease Following Radioembolization

Cancers ◽

10.3390/cancers13091992 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1992

Author(s):

Max Seidensticker ◽

Matthias Philipp Fabritius ◽

Jannik Beller ◽

Ricarda Seidensticker ◽

Andrei Todica ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Liver Disease ◽

Positive Impact ◽

Metastatic Breast ◽

Normal Liver ◽

Liver Parenchyma ◽

Breast Cancer Patients ◽

Radiation Induced ◽

The Impact

Background: Radioembolization (RE) with yttrium-90 (90Y) resin microspheres yields heterogeneous response rates in with primary or secondary liver cancer. Radiation-induced liver disease (RILD) is a potentially life-threatening complication with higher prevalence in cirrhotics or patients exposed to previous chemotherapies. Advances in RILD prevention may help increasing tolerable radiation doses to improve patient outcomes. This study aimed to evaluate the impact of post-therapeutic RILD-prophylaxis in a cohort of intensely pretreated liver metastatic breast cancer patients; Methods: Ninety-three patients with liver metastases of breast cancer received RE between 2007 and 2016. All Patients received RILD prophylaxis for 8 weeks post-RE. From January 2014, RILD prophylaxis was changed from ursodeoxycholic acid (UDCA) and prednisolone (standard prophylaxis [SP]; n = 59) to pentoxifylline (PTX), UDCA and low-dose low molecular weight heparin (LMWH) (modified prophylaxis (MP); n = 34). The primary endpoint was toxicity including symptoms of RILD; Results: Dose exposure of normal liver parenchyma was higher in the modified vs. standard prophylaxis group (47.2 Gy (17.8–86.8) vs. 40.2 Gy (12.5–83.5), p = 0.017). All grade RILD events (mild: bilirubin ≥ 21 µmol/L (but <30 μmol/L); severe: (bilirubin ≥ 30 µmol/L and ascites)) were observed more frequently in the SP group than in the MP group, albeit without significance (7/59 vs. 1/34; p = 0.140). Severe RILD occurred in the SP group only (n = 2; p > 0.1). ALBI grade increased in 16.7% patients in the MP and in 27.1% patients in the SP group, respectively (group difference not significant); Conclusions: At established dose levels, mild or severe RILD events proved rare in our cohort. RILD prophylaxis with PTX, UDCA and LMWH appears to have an independent positive impact on OS in patients with metastatic breast cancer and may reduce the frequency and severity of RILD. Results of this study as well as pathophysiological considerations warrant further investigations of RILD prophylaxis presumably targeting combinations of anticoagulation (MP) and antiinflammation (SP) to increase dose prescriptions in radioembolization.

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Associations of one-carbon metabolism-related gene polymorphisms with breast cancer risk are modulated by diet, being higher when adherence to the Mediterranean dietary pattern is low

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06108-8 ◽

2021 ◽

Author(s):

Shang Cao ◽

Zheng Zhu ◽

Jinyi Zhou ◽

Wei Li ◽

Yunqiu Dong ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Carbon Metabolism ◽

Dietary Pattern ◽

Gene Polymorphisms ◽

Related Gene ◽

Mediterranean Dietary Pattern ◽

The Mediterranean ◽

One Carbon Metabolism

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Pterostilbene Changes Epigenetic Marks at Enhancer Regions of Oncogenes in Breast Cancer Cells

Antioxidants ◽

10.3390/antiox10081232 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1232

Author(s):

Sadaf Harandi-Zadeh ◽

Cayla Boycott ◽

Megan Beetch ◽

Tony Yang ◽

Benjamin J. E. Martin ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Dna Methyltransferase ◽

Epigenetic Marks ◽

Chip Sequencing ◽

Dietary Polyphenols ◽

A Genome ◽

Epigenetic Patterns

Epigenetic aberrations are linked to sporadic breast cancer. Interestingly, certain dietary polyphenols with anti-cancer effects, such as pterostilbene (PTS), have been shown to regulate gene expression by altering epigenetic patterns. Our group has proposed the involvement of DNA methylation and DNA methyltransferase 3B (DNMT3B) as vital players in PTS-mediated suppression of candidate oncogenes and suggested a role of enhancers as target regions. In the present study, we assess a genome-wide impact of PTS on epigenetic marks at enhancers in highly invasive MCF10CA1a breast cancer cells. Following chromatin immunoprecipitation (ChIP)-sequencing in MCF10CA1a cells treated with 7 μM PTS for 9 days, we discovered that PTS leads to increased binding of DNMT3B at enhancers of 77 genes, and 17 of those genes display an overlapping decrease in the occupancy of trimethylation at lysine 36 of histone 3 (H3K36me3), a mark of active enhancers. We selected two genes, PITPNC1 and LINC00910, and found that their enhancers are hypermethylated in response to PTS. These changes coincided with the downregulation of gene expression. Of importance, we showed that 6 out of 17 target enhancers, including PITPNC1 and LINC00910, are bound by an oncogenic transcription factor OCT1 in MCF10CA1a cells. Indeed, the six enhancers corresponded to genes with established or putative cancer-driving functions. PTS led to a decrease in OCT1 binding at those enhancers, and OCT1 depletion resulted in PITPNC1 and LINC00910 downregulation, further demonstrating a role for OCT1 in transcriptional regulation. Our findings provide novel evidence for the epigenetic regulation of enhancer regions by dietary polyphenols in breast cancer cells.

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DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

Nature Communications ◽

10.1038/s41467-021-22665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Wendan Ren ◽

Huitao Fan ◽

Sara A. Grimm ◽

Jae Jin Kim ◽

Linhui Li ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Histone H3 ◽

Genomic Stability ◽

Mammalian Genome ◽

Dna Methyltransferase 1 ◽

Chromatin Modifications ◽

Direct Link ◽

Histone H4 ◽

Radiation Induced

AbstractDNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

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A radiosensitizer, gallotannin-rich extract from Bouea macrophylla seeds, inhibits radiation-induced epithelial-mesenchymal transition in breast cancer cells

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03363-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jiraporn Kantapan ◽

Siwaphon Paksee ◽

Aphidet Duangya ◽

Padchanee Sangthong ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Breast Cancer Cell Lines ◽

Mesenchymal Transition ◽

Mammosphere Formation ◽

Radiation Induced

Abstract Background Radioresistance can pose a significant obstacle to the effective treatment of breast cancers. Epithelial–mesenchymal transition (EMT) is a critical step in the acquisition of stem cell traits and radioresistance. Here, we investigated whether Maprang seed extract (MPSE), a gallotannin-rich extract of seed from Bouea macrophylla Griffith, could inhibit the radiation-induced EMT process and enhance the radiosensitivity of breast cancer cells. Methods Breast cancer cells were pre-treated with MPSE before irradiation (IR), the radiosensitizing activity of MPSE was assessed using the colony formation assay. Radiation-induced EMT and stemness phenotype were identified using breast cancer stem cells (CSCs) marker (CD24−/low/CD44+) and mammosphere formation assay. Cell motility was determined via the wound healing assay and transwell migration. Radiation-induced cell death was assessed via the apoptosis assay and SA-β-galactosidase staining for cellular senescence. CSCs- and EMT-related genes were confirmed by real-time PCR (qPCR) and Western blotting. Results Pre-treated with MPSE before irradiation could reduce the clonogenic activity and enhance radiosensitivity of breast cancer cell lines with sensitization enhancement ratios (SERs) of 2.33 and 1.35 for MCF7 and MDA-MB231cells, respectively. Pretreatment of breast cancer cells followed by IR resulted in an increased level of DNA damage maker (γ-H2A histone family member) and enhanced radiation-induced cell death. Irradiation induced EMT process, which displayed a significant EMT phenotype with a down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker vimentin in comparison with untreated breast cancer cells. Notably, we observed that pretreatment with MPSE attenuated the radiation-induced EMT process and decrease some stemness-like properties characterized by mammosphere formation and the CSC marker. Furthermore, pretreatment with MPSE attenuated the radiation-induced activation of the pro-survival pathway by decrease the expression of phosphorylation of ERK and AKT and sensitized breast cancer cells to radiation. Conclusion MPSE enhanced the radiosensitivity of breast cancer cells by enhancing IR-induced DNA damage and cell death, and attenuating the IR-induced EMT process and stemness phenotype via targeting survival pathways PI3K/AKT and MAPK in irradiated breast cancer cells. Our findings describe a novel strategy for increasing the efficacy of radiotherapy for breast cancer patients using a safer and low-cost natural product, MPSE.

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