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Estradiol Hypersensitivity and Mitogen-Activated Protein Kinase Expression in Long-Term Estrogen Deprived Human Breast Cancer Cells in Vivo¹

Departments of Internal Medicine (W.-S.S, W.Y, J.-P.W., R.J.S.) and Health Evaluation Sciences (M.C.) University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Department of General Surgery (S.M.), Keio University School of Medicine, Tokyo, Japan; and Laboratory of Cell Growth Regulation (R.K.), University of Texas MD Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Richard J. Santen, Division of Endocrinology, Department of Medicine, Box 334, University of Virginia Health Science Center, Charlottesville, Virginia 22908. E-mail: rjs5y{at}virginia.edu

Women with breast cancer who have responded to initial hormonal therapy frequently experience additional remissions upon further endocrine manipulation. We postulate that hypersensitivity to estradiol (E₂) may serve as a mechanistic explanation for these secondary responses. We previously provided evidence of hypersensitivity using an in vitro breast cancer model system and demonstrated the role of mitogen-activated protein kinase (MAP kinase) in the process of adaptation to long-term estradiol deprivation. In the present study, we wished to demonstrate that hypersensitivity to E₂ could occur under more complex in vivo conditions and that MAP kinase activation is enhanced under these circumstances. We used an MCF-7 breast cancer model system involving long-term estradiol deprived (LTED) cells to produce xenografts in nude mice and an E₂ clamp method to precisely control sex steroid levels. The E₂ clamp was designed to maintain plasma E₂ at a series of doubling doses from 1.25 pg/ml to 20.0 pg/ml in oophorectomized nude mice. As evidence of the validity of the clamp method, a uterine weight bioassay revealed an excellent, linear dose-response relationship between the predicted level of plasma E₂ and stimulation of uterine weight. As evidence of hypersensitivity, we found that LTED xenograft tumors grew to a greater extent than wild-type in response to E₂ concentrations of 1.25pg/ml (P = 0.003) and 2.5 pg/ml (P = 0.0002). At the 10.0 and 20.0 pg/ml plasma concentrations, the LTED tumors were stimulated to a lesser extent than the wild-type. This pattern of increased growth at lower concentrations and reduced growth vs. the wild-type at higher concentrations mimics closely the pattern seen for LTED cells in vitro. All LTED cell tumors exhibited enhanced activation of MAP kinase ranging from 18 to 25%, and E₂ did not increase this further. In contrast, E₂ caused a linear increase in the percentage of activated MAP kinase positive cells (P < 0.0001) in wild-type tumors from basal levels of 2.66% to maximal levels of 6.40%. These observations suggest a dynamic interplay whereby activation of MAP kinase renders cells more sensitive to the proliferative effects of E₂. The precise mechanisms for this interplay are unknown but, when further understood, could potentially provide insight into approaches to prevent the evolution of tumors to a hormone insensitive state.

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