Hypermethylation pattern of ESR and PgR genes and lacking estrogen and progesterone receptors in human breast cancer tumors: ER/PR subtypes

Article type: Research Article

Authors: Pirouzpanah, Saeed^{a; b; c; *} | Taleban, Forough-Azam^c | Mehdipour, Parvin^{d; *} | Sabour, Siamak^e | Atri, Morteza^f

Affiliations: [a] Department of Biochemistry and Dietetics, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran | [b] Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran | [c] Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran | [d] Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran | [e] Safety Promotion and Injury Prevention Research Centre, Department of Clinical Epidemiology, Faculty of Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran | [f] Cancer Institute, Tehran University of Medical Sciences/Day General Hospital, Tehran, Iran

Correspondence: [*] Corresponding authors: Saeed Pirouzpanah, Department of Biochemistry and Dietetics, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. Tel.: +98 912 3490037; Fax: +98411 3340634; E-mail: pirouzpanah@gmail.com.ParvinMehdipour,DepartmentofMedicalGenetics,SchoolofMedicine,TehranUniversityofMedicalSciences,Tehran,Iran.E-mail:mehdipor@tums.ac.ir.

Abstract: BACKGROUND: The option of endocrine therapy in breast cancer remains conventionally promising. OBJECTIVE: We aimed to investigate how accurately the pattern of hypermethylation at estrogen receptor (ESR) and progesterone receptor (PgR) genes may associate with relative expression and protein status of ER, PR and the combinative phenotype of ER/PR. METHODS: In this consecutive case-series, we enrolled 139 primary diagnosed breast cancer. Methylation specific PCR was used to assess the methylation status (individual test). Tumor mRNA expression levels were evaluated using real-time RT-PCR. Immunohistochemistry data was used to present hormonal receptor status of a tumor (as test reference). RESULTS: Methylation at ESR1 was comparably frequent in ER-breast tumors (83.0%, P< 0.001; sensitivity = 83.0%, specificity = 65.2% and diagnostic odds ratio, DOR = 12.0) and strongly correlated with ER-/PR- conditions (Cramer’s V= 0.44, P< 0.001). Methylated PgRb promoter frequently was observed in tumors recognised as ER- or negative ER/PR (77.1%, P< 0.01). Assessment of DNA methylation of ESR1 harbouring methylation at PgRb was a case significantly suggested to be able to detect the lack of ER/PR expressions (55.6%, P< 0.01; sensitivity = 80.6%, specificity = 68.7% and DOR = 8.7). However, methylated PgRb was quite acceptable determinant to contribute with methylated ESR1 to rank tumors as ER-/PR- (64.4%, P< 0.01; sensitivity = 78.0%, specificity = 62.5% and DOR = 6.0). CONCLUSIONS: Despite the methylation status of ESR1 showed preponderant contribution to tumoral phenotypes of ER- and ER-/PR-, the hypermethylation of PgRb seem another epigenetic signalling variable actively associate with methylated ESR1 to show lack of ER+/PR+ tumors in breast cancer.

Keywords: Breast cancer, hypermethylation, estrogen receptor, progestrone receptor

DOI: 10.3233/CBM-170697

Journal: Cancer Biomarkers, vol. 21, no. 3, pp. 621-638, 2018