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Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers

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Abstract

Estrogen receptor α (ER) and its ligand estrogen play vital roles in the development, progression and treatment of breast cancer. An increasing number of studies have also provided evidence linking disruption of the Fanconi anemia/BRCA cascade to breast cancer. Our objectives were to examine the methylation status and expression profiles of ER, correlate the findings with BRCA1 and FANCF methylation and map the critical CpGs for ER expression. We found that the CpG islands in the 5′ region of the ER gene are methylated in 59 of 120 (49.2%) primary breast cancers, including 45 of 59 ER-negative tumors (76.3%, P < 0.00001). In addition, we observed a strong correlation between ER promoter and BRCA1 promoter methylation (odds ratio 3.12, 95% confidence interval 1.10–9.68, P = 0.02). In contrast, FANCF methylation was rare in breast tumors: one of 120 (0.8%). ER methylation was associated with high tumor grade (60.4% methylated vs. 39.6% unmethylated in grade 3 tumors, P = 0.04) and tumor subtype (P = 0.03). Though small in number, all tumors of the medullary subtype were ER methylated. In contrast, the lobular subtype had the least methylation (23.1% methylated vs. 76.9% unmethylated). After treatment of MDA-MB-231 cells with 5-aza-cytidine (5-aza-dC) and trichostatin, which resulted in re-expression of ER mRNA, we localized dramatic demethylation effects to CpG islands in positions +68, +165, +192, +195, +337, +341 and +405 from transcription start site of the ER promoter. These data suggest that unlike FANCF, both ER and BRCA1 are specifically targeted for methylation in sporadic breast cancers, a phenomenon that should be explored for development of novel diagnostic and therapeutic approaches.

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Acknowledgments

O.I. Olopade is supported by National Institute of Environmental Health Sciences grant P50 ES012382, NIH-National Cancer Institute Cancer Center Support grant 3P30 CA 23074, the Breast Cancer Research Foundation, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Ralph and Marion Falk Medical Research Trust. O.I. Olopade is a Doris Duke Distinguished Clinical Scientist.

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Authors and Affiliations

  1. Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, 60637-1463, USA

    Minjie Wei, Jinhua Xu, Rita Nanda, Lise Sveen, James Fackenthal, Tatyana A. Grushko & Olufunmilayo I. Olopade

  2. Department of Pharmacology, China Medical University, Shenyang, Liaoning, 110001, People’s Republic of China

    Minjie Wei

  3. Department of Health Studies, University of Chicago, Chicago, IL, 60637-1463, USA

    James Dignam

  4. Department of Human Genetics, University of Chicago, Chicago, IL, 60637-1463, USA

    Olufunmilayo I. Olopade

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  1. Minjie Wei
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Correspondence to Olufunmilayo I. Olopade.

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M. Wei and J. Xu contributed equally.

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Wei, M., Xu, J., Dignam, J. et al. Estrogen receptor α, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers. Breast Cancer Res Treat 111, 113–120 (2008). https://doi.org/10.1007/s10549-007-9766-6

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  • DOI: https://doi.org/10.1007/s10549-007-9766-6

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