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Abstract
Breast cancer (BC) is the multifactorial disease where different genes play the major pathogenic role with tumor-suppressor genes in particular. These genes methylation is supposed to be the common regulation mechanism.
The aim of the present paper is to study methylation in group of tumor-suppressor genes: RASSF1A, SEMA3B, RARP2, RHOA, GPX1 and NKIRAS1 in luminal and mioepithelial breast cancer, and to evaluate their correlation with clinical subtype's course of this disease.
Methods. Analysis of methylation was done in group of 174 malignant/normal breast tissue pairs and of 10 health breast tissue samples. Two independent methods a methyl-specific PCR (RASSF1A, RARP2, SEMA3B) and methylation-sensitive restriction analysis (RHOA, GPX1, NKIRAS were used.
Results. A statistically significant high methylation frequency for genes RASSF1A, SEMA3B and RAR-p2 were shown (the positive ratio ranged from 13.2% to 37.9%) compared with normal breast tissue (the positive ratio ranged 0-6.9%, respectively), (p<0.00001). We revealed high frequent methylation level of RAR-P2 gene that was significantly higher in the luminal subtype B with the over expression of Her2 and Ki-67 compared with Her2-negative type and low level of Ki-67 (44% vs. 23.1%, p = 0.0458 and 38.5% vs. 16.2%, p = 0.0059, respectively). Interestingly we report that 5 and 10 years survivability without methylation was 93.5%, 85.5%, and 91.3%, 83.7%, respectively, compared ones with methylation where was lower 80.3 %, 65.3% (p = 0.007) and 84.3%, 67.2% (р=0,038) respectively.
Conclusion. Methylation of RASSF1A, SEMA3B, RAR-P2, GPX1, RHOA и NKIRAS1 genes plays important role in tumorigenesis of luminal breast cancer by modulating their functions. Methylation of the RASSF1A and RAR-P2 genes is associated with an unfavorable the disease outcome. Identified epigenetic alterations in luminal subtypes BC could be included in the biomarker system to improve in evaluating diagnosis, prognosis of disease, especially for choosing the individual tactics of treatment.
References
Логинов В.И., Пронина И.В., Бурденный А.М. и др. Роль метилирования в регуляции экспрессии функционально значимых генов хромосомы 3: RHoA, GPX1, USP4, DAG1, NKIRAS1 - в опухолях молочной железы // Молекулярная медицина. - 2014. - № 6. - C. 30-37.
Пронина И.В., Логинов В.И., Ходырев Д.С. и др. Уровень экспрессии гена RASSF1A в первичных эпителиальных опухолях разной локализации // Молекулярная биология. - 2012. - Т. 46. - № 2. - С. 260-268.
Braga Е., Loginov W., Khodyrev D. et al. A novel MECA3 region in human 3p21.3 harboring putative tumor suppressor genes and oncogenes // Exp. Oncol. - 2011. - Vol. 33. - № 1. - P. 33-41.
Braga E., Senchenko V., Bazov I. et al. Critical tumor-suppressor gene regions on chromosome 3p regions in major human epithetlial malignancies: allelotyping and quantitative real time PCR // Int. J. Cancer. - 2002. -Vol. 100. - № 5. - P. 534-541. - DOI: 10.1002/ijc.10511
Gerashchenko G.V., Bogatyrova O.O., Rudenko E.E. et al. Genetic and epigenetic changes of NKIRAS1 gene in human renal cell carcinomas // Exp. Oncol. - 2010. - Vol. 32. - № 2. - С. 71-75.
Dmitriev A.A., Kashuba V.I., Haraldson K. et al. Genetic and epigenetic analysis of non-small cell lung cancer with Notl-microarrays // Epigenetics. - 2012. - Vol. 7. - № 5. - С. 502-513. - DOI: 10.4161/epi.19801
Dreijerink K., Braga E., Kuzmin I. et al. The candidate tumor suppressor gene, RAssF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis // Proc. Natl. Acad. Sci. USA. - 2001. - Vol. 98. - № 13. - P. 7504-7509. - DOI: 10.1073/pnas.131216298
Kashuba V., Dmitriev A.A., Krasnov G.S. et al. Notl Microarrays: Novel epigenetic markers for early detection and prognosis of high grade serous ovarian cancer // Int. J. Mol. Sci. - 2012. - Vol. 13. - № 10. - С. 13352-13377. - DOI: 10.3390/ijms131013352
Kajabova V., Smolkova B., Zmetakova I. et al. RASSF1A Promoter Methylation Levels Positively Correlate with Estrogen Receptor Expression in Breast Cancer Patients // Transl Oncol. - 2013. - Vol. 6. - № 3. - Р 297-304.
Pronina I.V., Loginov V.I., Burdennyy A.M. et al. Expression and DNA methylation alterations of seven cancer-associated 3p Genes and their predicted regulator miRNAs (miR-129-2, miR-9-1) in breast and ovarian cancers // Gene. - 2016. - Vol. 576 (1 Pt 3). - P 483-491. - DOI: 10.1016/j.gene.2015.10.059
Chen R., Zhuge X., Huang Z. et al. Analysis of SEMA3B methylation and expression patterns in gastric cancer tissue and cell lines // Oncol Rep. - 2014. - Vol. 31. - № 3. - Р 1211-1218. - DOI: 10.3892/or.2014.2972
Cornen S., Guille A., Ad lade J. et al. Candidate luminal B breast cancer genes identified by genome, gene expression and DNA methylation profiling // PLoS One. - 2014. -Vol. 9. - № 1. - Р 1-16. - DOI: 10.1371/journal.pone.0081843
Donninger H., Schmidt M.L., Mezzanotte J., Barnoud T, Clark G.J. Ras signaling through RASSF proteins // Semin Cell Dev Biol. - 2016. - Vol. 58. - P 86-95. - DOI: 10.1016/j.semcdb.2016.06.007
Feng W., Shen L., Wen S. et al. Correlation between CpG methylation profiles and hormone receptor status in breast cancers // Breast Cancer Res. - 2007. - Vol. 9. -№ 4. -R57. - DOI: 10.1186/bcr1762
Feil R., Fraga M.F. Epigenetics and the environment: emerging patterns and implications // Nat. Rev. Genet. - 2011. - Vol. 13. - № 2. - Р 97-109. - DOI: 10.1038/nrg3142
Harrison S.M., Knifley T., Chen M., O'Connor K.L. LPA, HGF, and EGF utilize distinct combinations of signaling pathways to promote migration and invasion of MDA-MB-231 breast carcinoma cells // BMC Cancer. - 2013. - Vol. 13. - e501. - DOI: 10.1186/1471-2407-13-501
Hon G.C., Hawkins R.D., Caballero O.L. et al. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer // Genome Res. - 2012. - Vol. 22. - № 2. - P. 246-258. - DOI: 10.1101/gr.125872.111
Jones PA., Baylin S.B. The epigenomics of cancer.. // Cell. - 2007. - Vol. 128. - № 4. - Р 683-692. - DOI: 10.1016/j.cell.2007.01.029
Kagohara L.T., Stein-O'Brien G.L., Kelley D. et al. Epigenetic regulation of gene expression in cancer: techniques, resources and analysis // Brief Funct Genomics. - 2017. - P 1-15. - DOI: 10.1093/bfgp/elx018
Kulak M.V., Cyr A.R., Woodfield G.W. et al. Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer // Oncogene. -2013. - Vol. 32. - № 34. - Р 4043-3051. - 10.1038/onc.2012.400
Lester S.C., Bose S., Chen YY et al. Members of the Cancer Committee, College of American Pathologists. Protocol for the examination of specimens from patients with invasive carcinoma of the breast // Arch Pathol. Lab Med. - 2009. - Vol. 133. - №10. - Р 1515-1538. - DOI: 10.1043/1543-2165-133.10.1515
Lubos E., Loscalzo J., Handy D.E. Glutathione peroxidase-1 in health and disease: from molecular mechanisms to therapeutic opportunities // Antioxid Redox Signal. -2011. - Vol. 15. - № 7. - Р 1957-1997. - DOI: 10.1089/ars.2010.3586
Mencalha A., Victorino V.J., Cecchini R., Panis C. Mapping oxidative changes in breast cancer: understanding the basic to reach the clinics // Anticancer Res. - 2014. -Vol. 34. - № 3. - Р 11271140.
Neufeld G., Mumblat Y, Smolkin T. et al. The role of the semaphorins in cancer // Cell Adh Migr. - 2016. - Vol. 10. - № 6. - P 652-674. - DOI: 10.1080/19336918.2016.1197478
Pappas J.J., Toulouse A., Hebert J. et al. Allelic methylation bias of the RARB2 tumor suppressor gene promoter in cancer // Genes Chromosomes Cancer. - 2008. - Vol. 47. - № 11. - Р 978-993. - DOI: 10.1002/gcc.20603
Park S.Y, Kwon H.J., Choi Y et al. Distinct patterns of promoter CpG island methylation of breast cancer subtypes are associated with stem cell phenotypes // Mod Pathol. - 2012. - Vol. 25. - № 2. - P 185-196. - DOI: 10.1038/modpathol.2011.160
Ridley A.J. RhoA, RhoB and RhoC have different roles in cancer cell migration // J. Microsc. - 2013. - Vol. 251. -№ 3. - P 242-249. - DOI: 10.1111/jmi.12025
Sunami E., Shinozaki M., Sim M.S. et al. Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors // Breast Cancer Res. - 2008. - Vol. 10. - № 3. - R46. - DOI: 10.1186/bcr2098
Tavassoli F.A., Devilee P. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. IARC Press: Lyon 2003. https://www.iarc.fr/en/publications/ pdfs-online/pat-gen/bb4/BB4.pdf.
Wu L., Shen Y, Peng X. et al. Aberrant promoter methylation of cancer-related genes in human breast cancer // Oncol Lett. - 2016. - Vol. 12. - № 6. - P. 5145-5155. - DOI: 10.3892/ol.2016.5351
Xu J., Shetty P.B., Feng W. et al. Methylation of HIN-1, RASSF1A, RIL and CDH13 in breast cancer is associated with clinical characteristics, but only RASSF1A methylation is associated with outcome // BMC Cancer. -2012. - Vol. 12. - P. 243. - DOI: 10.1186/1471-2407-12-243
Yamamoto N., Nakayama T, Kajita M. et al. Detection of aberrant promoter methylation of GSTP1, RASSF1A, and RARbeta2 in serum DNA of patients with breast cancer by a newly established one-step methylation-specific PCR assay // Breast Cancer Res Treat. - 2012. - Vol. 132. -№ 1. - P. 165-173. - DOI: 10.1007/s10549-011-1575-2
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