Breast Cancer: Cardiotoxicity caused by anthracyclines More Prominent

Breast Cancer: Cardiotoxicity caused by anthracyclines More Prominent

Breast Cancer: Cardiotoxicity caused by anthracyclines More Prominent.  SABCS | Whole-gene association study illuminates the dark side of chemotherapy: rs28714259 in the mechanism of anthracycline-induced cardiotoxicity. 

Anthracyclines are one of the most commonly used chemotherapeutics for breast cancer. With the prolonged survival time of breast cancer patients, the cardiotoxicity caused by anthracyclines has become increasingly prominent.

The San Antonio Breast Cancer Conference (SABCS) is one of the most influential breast cancer conferences, aiming to provide international academia, physicians and researchers with cutting-edge information about breast cancer and precancerous breast diseases. The SABCS2020 conference announcement summary contains no lack of oncology cardiology content. This column is jointly launched by Sandu Medical and Zhejiang Oncology and Cardiology Collaboration Group (ZOC). It is selected, compiled and shared; medical colleagues are welcome to follow and leave comments at the end of the article.

【PS13-22】Shedding light on the dark side of chemo: Post-GWAS functional studies of rs28714259 in anthracycline-induced cardiotoxicity

Xi Wu1, Gloria Xue2, Fei Shen1, Guanglong Jiang1, Santosh Philips1, Geneva Cunningham1, Erica Cantor1 and Bryan P Schneider1. 1Indiana University School of Medicine, Indianapolis, IN; 2Indiana University, Bloomington, IN

Anthracyclines are commonly used chemotherapy drugs for breast cancer treatment, but they may cause dose-related cardiotoxicity and cause congestive heart failure (CHF) in 2% of patients. Although different mechanisms of anthracyclines causing cardiotoxicity have been proposed, the exact molecular pathogenesis has not yet been fully elucidated. In addition, there are no clinically effective biomarkers to predict cardiotoxicity.

Previously, we have identified and verified rs28714259 (G/A) single nucleotide polymorphism (SNP) and anthracyclines in three large-scale phase III breast cancer auxiliary clinical studies through genome-wide association analysis (GWAS) The association with the risk of induced CHF. rs28714259 (G/A) is located in the glucocorticoid receptor (GR) response element, and the risk allele (A) is expected to disrupt GR binding. In the mouse model, dexamethasone activates the GR signaling pathway to protect cardiomyocytes from apoptosis caused by doxorubicin.

Research points

In order to study the role of rs28714259 in GWAS after CHF, we began to investigate whether rs28714259 regulates the GR signaling pathway through the allelic GR enhancer activity. We cloned a 1kb DNA sequence containing wild type (G) or risk allele (A) on both sides of rs28714259 into the luciferase reporter plasmid.

● Luciferase analysis showed that after 100nm dexamethasone activated the GR activity of iPSC-derived cardiomyocytes (iPSC-CMs), compared with the control vector without enhancer, the activity of wild-type cardiomyocytes increased by 60%. The transfection risk allele iPSC-CM did not show an increase in luciferase activity, suggesting that the A allele blocked GR-mediated transcriptional activation.

● The electrophoretic mobility experiment (EMSA) was used to analyze the nuclear extract of dexamethasone-treated iPSC-CM, and we observed significant band changes of G or A allele probes. In addition, the hypershift band with GR antibody was also observed, confirming that GR did bind to the rs28714259 region. It is worth noting that compared with the wild type, the band intensity of the risk allele probe is reduced by 50%, which indicates that the binding affinity of GR and the risk allele probe is weak, which is consistent with the decrease in transcriptional activity.

● Finally, in order to identify the genes regulated by rs28714259 under anthracycline exposure, we performed RNA-Seq analysis on iPSC-CMs of each genotype. RNA-Seq data shows that the most significant differential regulatory network is the death receptor pathway including FADD, FAS, and Caspase-8. These factors cause doxorubicin-induced apoptosis. In addition, 11 genes in the GR signaling pathway are also regulated by rs28714259.

In conclusion, this study shows that the rs28714259 variant may have allele-specific GR enhancer activity and regulate genes involved in doxorubicin-induced apoptosis.

Editor’s comments:

Anthracyclines are one of the most commonly used chemotherapeutics for breast cancer. With the prolonged survival time of breast cancer patients, the cardiotoxicity caused by anthracyclines has become increasingly prominent. A large meta-analysis showed that compared with chemotherapy without doxorubicin, the cardiotoxicity and deaths caused by cardiovascular disease caused by doxorubicin-containing chemotherapy were significantly increased. Genome-wide Association Study (GWAS) is the use of high-throughput gene chip technology to conduct an overall association analysis of common genetic variations-single nucleotide polymorphism (SNP) and copy number variation (CNV) in the human genome, and find the impact A new strategy for gene mutation of complex traits.

The authors of this study previously identified and verified the relationship between rs28714259 (G/A) single nucleotide polymorphism (SNP) and the risk of anthracycline-induced congestive heart failure in a large-scale phase III breast cancer auxiliary clinical study through GWAS. relationship. In this study, the post-GWAS function study further clarified the role and possible mechanism of rs28714259 in doxorubicin-induced apoptosis. This study provides a new research method to further clarify the role of different mechanisms in the cardiotoxicity caused by anthracyclines, and also provides potential biomarkers for clinically identifying high-risk groups of anthracyclines causing cardiotoxicity. It is worthy of further development. In-depth study.

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