The epigenetic silencing of the estrogen receptor (ER) by hypermethylation of the ESR1 promoter is seen predominantly in triple-negative breast cancers in Indian women
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The proportion of estrogen receptor (ER)-negative and triple-negative (TN) breast cancer in Indian women is higher than that reported in the West, and this difference persists even after their migration to the West. The causes for this significant difference are not entirely clear. Hypermethylation of the ER promoter, an epigenetic alteration, is known to be one of the mechanisms by which the expression of ER is suppressed. Two thirds of breast cancer specimens from an Indian center tested, using the highly sensitive, methylation-specific polymerase chain reaction (MSP) technique, were reported positive. We have used a quantitative assay, the MethyLight, to better assess the extent of methylation in the ESR1 promoter region in 98 breast cancer tumor specimens from Indian women. In addition, the amount of ER transcripts was determined by quantitative reverse transcriptase polymerase chain reaction. Using the stringent cutoff of at least 4% of the target sequence being methylated, 27% of TN tumors were methylated. In addition they demonstrated the highest levels of methylation. In contrast less than 2% ER-positive tumors were hypermethylated. While the proportion of hypermethylated tumors are lower in this study than that estimated using MSP, our results support the notion of increased epigenetic deregulations in ER-negative tumors in general and TN tumors in particular. The development of this assay also permits a rational approach to the selection of patients for clinical trials examining the efficacy of demethylating agents in the treatment of ER-negative breast cancer.
KeywordsQuantitative methylation Estrogen receptor promoter Triple-negative breast cancer Epigenetic FFPE
This work was funded by the Nadathur Holdings, Bangalore and the Bagaria Education Trust, Bangalore. The patient enrolment, sample collection, and patient follow-up were coordinated by Ms. Annie Alexander of “Aadhara”, our patient support group. We would also like to acknowledge the excellent technical support provided by Mr. Raju and Ms. Anupama as well as the meticulous collation of clinical information by Ms. Rohini our clinical research associate. Dr Tinku Thomas of the Epidemiology and Biostatistics division of SJRI reviewed the statistical analysis.
Conflicts of interest
- 4.National Cancer registry Programme. Consolidated report of the population based cancer registries 1990–1996. New Delhi: Indian Council of Medical Research; 2001.Google Scholar
- 5.Raina V, Taneja V, Gulati A, Deo SVS, Shukla NK, Vij U. Oestrogen receptor status in breast cancer. Indian Pract. 2000;53:405–7.Google Scholar
- 10.Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer. 2007;109:1721–8.PubMedCrossRefGoogle Scholar
- 13.Hicks DG, Short SM, Prescott NL, Tarr SM, Coleman KA, Yoder BJ, Crowe JP, Choueiri TK, Dawson AE, Budd GT, Tubbs RR, Casey G, Weil RJ. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5⁄6, and overexpress HER2 or EGFR. Am J Surg Pathol. 2006;30:1097–104.PubMedGoogle Scholar
- 14.Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, Hess KR, Stec J, Ayers M, Wagner P, Morandi P, Fan C, Rabiul I, Ross JS, Hortobagyi GN, Pusztai L, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11:5678–85.PubMedCrossRefGoogle Scholar
- 19.Yoshida T, Eguchi H, Nakachi K, Tanimoto K, Higashi Y, Suemasu K, Iino Y, Morishita Y, Hayashi S. Distinct mechanisms of loss of estrogen receptor α gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. Carcinogenesis. 2000;21:2193–201.PubMedCrossRefGoogle Scholar
- 20.Lapidus RG, Ferguson AT, Ottaviano YL, Parl FF, Smith HS, Weitzman SA, Baylin SB, Issa JP, Davidson NE. Methylation of estrogen and progesterone receptor gene 5′ CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumours. Clin Cancer Res. 1996;2:805–10.PubMedGoogle Scholar
- 29.Cronin M, Pho M, Dutta D, Stephans JC, Shak S, Kiefer MC, Esteban JM, Baker JB. Measurement of gene expression in archival paraffin-embedded tissues: development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. Am J Pathol. 2004;164:35–42.PubMedCrossRefGoogle Scholar
- 31.Gaudet MM, Campan M, Figueroa JD, Yang XR, Lissowska J, Peplonska B, Brinton LA, Rimm DL, Laird PW, Garcia-Closas M, Sherman ME. DNA hypermethylation of ESR1 and PGR in breast cancer: pathologic and epidemiologic associations. Cancer Epidemiol Biomarkers Prev. 2009;18(11):3036–4.PubMedCrossRefGoogle Scholar
- 34.Bediaga NG, Acha-Sagredo A, Guerra I, Viguri A, Albaina C, Ruiz Diaz I, Rezola R, Alberdi MJ, Dopazo J, Montaner D, de Renobales M, Fernández AF, Field JK, Fraga MF, Liloglou T, de Pancorbo MM. DNA methylation epigenotypes in breast cancer molecular subtypes. Breast Cancer Res. 2010;12:R77.PubMedCrossRefGoogle Scholar