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Methylation of the Estrogen Receptor Gene CpG Island Marks Loss of Estrogen Receptor Expression in Human Breast Cancer Cells¹

Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 [Y. L. O., J-P. I., S. B. B., N. E. D.]; Department of Pathology, Vanderbilt University, Nashville, Tennessee 37232 [F. F. P.]; and Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, California 94115 [H. S. S.]

Breast cancer is the most common malignancy in women and hormone resistance is a challenging problem in its treatment. Loss of estrogen receptor expression is an important means of hormone resistance, but the mechanisms involved are poorly understood. We now demonstrate a potential role for abnormal DNA methylation in transcriptional inactivation of the estrogen receptor gene. Estrogen receptor-negative human breast cancer cells growing in culture lack estrogen receptor mRNA, have a higher capacity to methylate DNA, and display extensive methylation of the CpG island in the 5' promoter region of the estrogen receptor gene, which would correlate with silencing of expression. These results suggest that abnormal methylation could account for transcriptional inactivation of the estrogen receptor gene and subsequent hormone resistance in some human breast cancers.

¹ This work was supported by NIH Grants P30 CA06973, R29 CA49634, R01 CA43318, and P01 CA44768; the Stetler Research Fund; and American Cancer Society Grant ACS PDT-371.

² To whom requests for reprints should be addressed, at The Johns Hopkins Oncology Center, 422 North Bond Street, Baltimore, MD 21231.

Received 3/ 4/94. Accepted 4/ 6/94.

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