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Endocrinology Vol. 139, No. 10 4164-4174
Copyright © 1998 by The Endocrine Society

ARTICLES

Estrogen Receptor Expression and Function in Long-Term Estrogen-Deprived Human Breast Cancer Cells1

Meei-Huey Jeng, Margaret A. Shupnik, Timothy P. Bender, Eric H. Westin, Debdutta Bandyopadhyay, Rakesh Kumar, Shigeru Masamura2 and Richard J. Santen

Department of Internal Medicine (M.-H.J., M.A.S., R.J.S.), Department of Microbiology (T.P.B.), University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Department of Medicine (E.H.W.), The Robert C. Byrd Health Science Center, West Virginia University, Morgantown, West Virginia 26506; Laboratory of Cell Growth Regulation, University of Texas M.D. Anderson Cancer Center (D.B., R.K.), Houston, Texas 77030; and Department of Medicine, Pennsylvania State University (S.M.), School of Medicine, Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Meei-Huey Jeng, Department of Internal Medicine, Division of Hematology/Oncology, University of Virginia Health Sciences Center, Box 513, Charlottesville, Virginia 22908. E-mail: mj5x{at}virginia.edu

Hormone-dependent breast cancer responds to primary therapies that block estrogen production or action, but tumor regrowth often occurs 12–18 months later. Additional hormonal treatments that further reduce estrogen synthesis or more effectively block its action cause additional remissions, but the mechanisms responsible for these secondary responses are not well understood. As a working hypothesis, we postulated that primary hormonal therapy induces adaptive changes, resulting in enhanced estrogen receptor (ER) expression and target gene activation and, further, that secondary treatment modalities interfere with these receptor-mediated transcriptional pathways.

To test this hypothesis, we used an MCF-7 breast cancer model system involving deprivation of estradiol in culture for a prolonged period. These long-term estradiol-deprived (LTED) cells adapt by acquiring the ability to regrow in the absence of added estradiol. The experimental paradigm involved the comparison of wild-type cells with LTED cells. As endpoints, we directly assessed ER expression at the messenger RNA-, protein-, and ligand-binding levels and ER functionality by quantitating reporter gene activation and expression of endogenous estrogen target gene messenger RNA, as well as ER coactivator levels.

Our data demonstrated an adaptive increase in ER expression and in basal ER functionality, as assessed by read-out of three different transfected reporters in LTED, as opposed to wild-type MCF-7 cells. Increased reporter gene read-out was dramatically inhibited by the pure antiestrogen ICI 182,780. As verification that endogenous (as well as transfected) estrogen target genes had enhanced transcription, we found that the basal levels of c-myb and c-myc message were substantially increased in LTED cells and could be inhibited by antiestrogen. Interestingly, the levels of c-myb and c-myc message in the LTED cells seemed to be increased out of proportion to the degree of ER reporter gene activation and were similar to those in wild-type cells maximally stimulated with estradiol. In addition, not all estrogen-responsive genes were activated, because transforming growth factor-{alpha} message level was not increased in LTED cells. Up-regulation of the steroid receptor coactivator SRC-1 did not seem to mediate the process of enhanced ER-induced transcription. Considering these observations together, we suggest that long-term estradiol deprivation causes adaptive processes that not only involve up-regulation of the ER but also influence the specificity and magnitude of activation of estrogen-responsive genes.




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