A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research

Abstract

Breast cancer patients are at a particularly high risk of cardiotoxicity from chemotherapy having a detrimental effect on quality-of-life parameters and increasing the risk of mortality. Prognostic biomarkers would allow the management of therapies to mitigate the risks of cardiotoxicity in vulnerable patients and a key potential candidate for such biomarkers are microRNAs (miRNA). miRNAs are post-transcriptional regulators of gene expression which can also be released into the circulatory system and have been associated with the progression of many chronic diseases including many types of cancer. In this review, the evidence for the potential application of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity (CIC) in breast cancer patientsis evaluated and a simple meta-analysis is performed to confirm the replication status of each reported miRNA. Further selection of miRNAs is performed by reviewing the reported associations of each miRNA with other cardiovascular conditions. Based on this research, the most representative panels targeting specific chemotherapy agents and treatment regimens are suggested, that contain several informative miRNAs, including both general markers of cardiac damage as well as those for the specific cancer treatments.

Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA

“…Cardiotoxicity is one of the most significant complications among breast cancer patients as a result of the use of agents such as anthracyclines and monoclonal antibodies directed against HER2. Therefore, the search for prognostic biomarkers of this event is crucial in mitigating the risk of cardiotoxicity in vulnerable patients [ 203 , 204 ]. Numerous microRNAs are considered among the candidates, including hsa-miR-1273 g-3p and hsa-miR-4638-3p (regulating TGF-β and CTGF pathways, responsible for atherosclerotic plaque instability and heart failure [ 205 ]), hsa-miR-208 (associated with fibrosis and EMT progression, and specifically targeted to the BMP co-receptor, endoglin [ 206 , 207 ]), hsa-miR-130a (associated with cardiomyopathy [ 208 , 209 , 210 ]), hsa-miR-29a (involved in hemolysis of blood cells [ 211 , 212 ]) or proangiogenic hsa-miR-17-5p, hsa-miR-19a, hsa-miR-378, hsa-Let-7b [ 208 , 209 ] and hsa-miR-126 [ 207 , 211 ].…”

Biological Implications of MicroRNAs as Regulators and Biomarkers of Therapeutic Toxicities in Breast Cancer

“…We have already mentioned the role of miRNAs in predicting response to chemotherapy [ 60 ], but can miRNAs be useful in predicting cardiotoxicity? One systematic review identified a range of miRNAs as markers of cardiac damage in breast cancer patients treated with chemotherapy, highlighting the important role of these molecules in side effect management [ 109 ]. Traditional biomarkers of cardiac function include natriuretic peptides [ 110 ] and troponin levels [ 111 ].…”

Cardiac miRNA expression during the development of chronic anthracycline-induced cardiomyopathy using an experimental rabbit model

“…Moreover, in vitro data cannot reliably describe the complex changes which develop slowly in clinical settings over many weeks or months. Indeed, several rodent in vivo studies as well as clinical trials have been performed in the past few years (see the review of Piegari et al, 2016 ; Ruggeri et al, 2018a ; Pereira et al, 2020 ; Chen and Xu, 2021 ; Brown et al, 2022 ). However, these studies have typically only concentrated on a few “cardiac enriched” miRNAs (e.g., miR-208, miR-1, and miR-133), while the presented results have been highly variable, possibly due to differences in dosage schedules, ANT administration, and the duration of the treatment ( Nishimura et al, 2015 ; Oliveira-Carvalho et al, 2015 ; Rigaud et al, 2017 ; Alves et al, 2022 ).…”

“…However, these studies have typically only concentrated on a few “cardiac enriched” miRNAs (e.g., miR-208, miR-1, and miR-133), while the presented results have been highly variable, possibly due to differences in dosage schedules, ANT administration, and the duration of the treatment ( Nishimura et al, 2015 ; Oliveira-Carvalho et al, 2015 ; Rigaud et al, 2017 ; Alves et al, 2022 ). A systematic review of the miRNAs that are currently used as plasma biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients suggest that three miRNA markers (miR-29a, miR-34a and miR-423) can be used as general cardiotoxicity indicators but should be supplemented with data concerning miR-1, miR-499 and miR-122 for patients receiving doxorubicin ( Brown et al, 2022 ).…”