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A Hypersensitive Estrogen Receptor- Mutation in Premalignant Breast Lesions¹

Breast Center, Baylor College of Medicine, Houston, Texas 77030 [S. A. W. F., T. H., S. H., S. M., P. O., D. C. A.]; Department of Internal Medicine, University Hospital of Vienna, Vienna, Austria 1090 [C. W.]; University of Alberta, Edmonton, Alberta, Canada TGG 2M7 [Q. X. Z.]; Department of Oncology, University Hospital, Lund, Sweden 22185 [Å. B.]; Science Department, Montana State University, Billings, Montana 59101 [C. G. C.]; and Department of Hematology, University of Texas Health Science Center, San Antonio, Texas 78248 [W. E. F.]

The best current model of breast cancer evolution suggests that most cancers arise from certain premalignant lesions. We have identified a common (34%) somatic mutation in the estrogen receptor (ER)- gene in a series of 59 typical hyperplasias, a type of early premalignant breast lesion. The mutation, which affects the border of the hinge and hormone binding domains of ER-, showed increased sensitivity to estrogen as compared with wild-type ER- in stably transfected breast cancer cells, including markedly increased proliferation at subphysiological levels of estrogen. The mutated ER- exhibits enhanced binding to the TIF-2 coactivator at low levels of hormone, which may partially explain its increased estrogen responsiveness. These data suggest that this mutation may promote or accelerate the development of cancer from premalignant breast lesions.

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