Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors
Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis...
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| author | Alexey I. Kalinkin Vladimir O. Sigin Ekaterina B. Kuznetsova Ekaterina O. Ignatova Ilya I. Vinogradov Maxim I. Vinogradov Igor Y. Vinogradov Dmitry V. Zaletaev Marina V. Nemtsova Sergey I. Kutsev Alexander S. Tanas Vladimir V. Strelnikov |
| author_facet | Alexey I. Kalinkin Vladimir O. Sigin Ekaterina B. Kuznetsova Ekaterina O. Ignatova Ilya I. Vinogradov Maxim I. Vinogradov Igor Y. Vinogradov Dmitry V. Zaletaev Marina V. Nemtsova Sergey I. Kutsev Alexander S. Tanas Vladimir V. Strelnikov |
| author_sort | Alexey I. Kalinkin |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the <i>LTB4R/LTB4R2</i> genes’ CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high <i>LTB4R/LTB4R2</i> expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the <i>LTB4R</i> and <i>LTB4R2</i> genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = −0.4, <i>p</i> = 2.6 × 10<sup>−6</sup>; R = −0.21, <i>p</i> = 0.015) and cg21886367 (R = −0.45, <i>p</i> = 7.3 × 10<sup>−8</sup>; R = −0.24, <i>p</i> = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan–Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated <i>LTB4R</i>. To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated <i>LTB4R/LTB4R2</i> genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating <i>LTB4R/LTB4R2</i> hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents. |
| first_indexed | 2024-03-08T20:42:14Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:42:14Z |
| publishDate | 2023-12-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e17a39ef166046e4a8d47b650602e2842023-12-22T14:14:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241734310.3390/ijms242417343Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast TumorsAlexey I. Kalinkin0Vladimir O. Sigin1Ekaterina B. Kuznetsova2Ekaterina O. Ignatova3Ilya I. Vinogradov4Maxim I. Vinogradov5Igor Y. Vinogradov6Dmitry V. Zaletaev7Marina V. Nemtsova8Sergey I. Kutsev9Alexander S. Tanas10Vladimir V. Strelnikov11Research Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaRegional Clinical Oncology Dispensary, 390011 Ryazan, RussiaDepartment of Histology, Pathological Anatomy and Medical Genetics, Ryazan State Medical University, 390026 Ryazan, RussiaDepartment of Histology, Pathological Anatomy and Medical Genetics, Ryazan State Medical University, 390026 Ryazan, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaResearch Centre for Medical Genetics, 115522 Moscow, RussiaTriple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the <i>LTB4R/LTB4R2</i> genes’ CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high <i>LTB4R/LTB4R2</i> expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the <i>LTB4R</i> and <i>LTB4R2</i> genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = −0.4, <i>p</i> = 2.6 × 10<sup>−6</sup>; R = −0.21, <i>p</i> = 0.015) and cg21886367 (R = −0.45, <i>p</i> = 7.3 × 10<sup>−8</sup>; R = −0.24, <i>p</i> = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan–Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated <i>LTB4R</i>. To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated <i>LTB4R/LTB4R2</i> genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating <i>LTB4R/LTB4R2</i> hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents.https://www.mdpi.com/1422-0067/24/24/17343breast cancerleukotriene receptorsDNA methylationXmaI-RRBS |
| spellingShingle | Alexey I. Kalinkin Vladimir O. Sigin Ekaterina B. Kuznetsova Ekaterina O. Ignatova Ilya I. Vinogradov Maxim I. Vinogradov Igor Y. Vinogradov Dmitry V. Zaletaev Marina V. Nemtsova Sergey I. Kutsev Alexander S. Tanas Vladimir V. Strelnikov Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors International Journal of Molecular Sciences breast cancer leukotriene receptors DNA methylation XmaI-RRBS |
| title | Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors |
| title_full | Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors |
| title_fullStr | Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors |
| title_full_unstemmed | Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors |
| title_short | Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors |
| title_sort | epigenomic profiling advises therapeutic potential of leukotriene receptor inhibitors for a subset of triple negative breast tumors |
| topic | breast cancer leukotriene receptors DNA methylation XmaI-RRBS |
| url | https://www.mdpi.com/1422-0067/24/24/17343 |
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