Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo
- PMID: 10614662
- DOI: 10.1210/endo.141.1.7270
Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo
Abstract
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 1.25 pg/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.
Similar articles
-
Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation.J Biol Chem. 2003 Aug 15;278(33):30458-68. doi: 10.1074/jbc.M305226200. Epub 2003 May 29. J Biol Chem. 2003. PMID: 12775708
-
Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells.Endocrinology. 1998 Oct;139(10):4164-74. doi: 10.1210/endo.139.10.6229. Endocrinology. 1998. PMID: 9751496
-
Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells.J Clin Endocrinol Metab. 1995 Oct;80(10):2918-25. doi: 10.1210/jcem.80.10.7559875. J Clin Endocrinol Metab. 1995. PMID: 7559875
-
Adaptive hypersensitivity to estradiol: potential mechanism for secondary hormonal responses in breast cancer patients.J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):115-25. doi: 10.1016/s0960-0760(01)00151-0. J Steroid Biochem Mol Biol. 2001. PMID: 11850215 Review.
-
Adaptive hypersensitivity to estrogen: mechanisms and clinical relevance to aromatase inhibitor therapy in breast cancer treatment.J Steroid Biochem Mol Biol. 2005 May;95(1-5):155-65. doi: 10.1016/j.jsbmb.2005.04.025. J Steroid Biochem Mol Biol. 2005. PMID: 16024245 Review.
Cited by 35 articles
-
Advances in Endocrine-Based Therapies for Estrogen Receptor-Positive Metastatic Breast Cancer.Drugs. 2019 Nov;79(17):1849-1866. doi: 10.1007/s40265-019-01208-8. Drugs. 2019. PMID: 31630379 Review.
-
Hormesis in Health and Chronic Diseases.Trends Endocrinol Metab. 2019 Dec;30(12):944-958. doi: 10.1016/j.tem.2019.08.007. Epub 2019 Sep 11. Trends Endocrinol Metab. 2019. PMID: 31521464 Review.
-
Estradiol Enables Chronic Corticosterone to Inhibit Pulsatile Luteinizing Hormone Secretion and Suppress Kiss1 Neuronal Activation in Female Mice.Neuroendocrinology. 2020;110(6):501-516. doi: 10.1159/000502978. Epub 2019 Aug 29. Neuroendocrinology. 2020. PMID: 31461711
-
Changes in GABAergic Transmission to and Intrinsic Excitability of Gonadotropin-Releasing Hormone (GnRH) Neurons during the Estrous Cycle in Mice.eNeuro. 2018 Nov 8;5(5):ENEURO.0171-18.2018. doi: 10.1523/ENEURO.0171-18.2018. eCollection 2018 Sep-Oct. eNeuro. 2018. PMID: 30417076 Free PMC article.
-
Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma.J Cancer Res Clin Oncol. 2018 Oct;144(10):1887-1897. doi: 10.1007/s00432-018-2717-2. Epub 2018 Jul 25. J Cancer Res Clin Oncol. 2018. PMID: 30046904
Publication types
MeSH terms
Substances
Grant support
LinkOut - more resources
-
Full Text Sources
-
Other Literature Sources
-
Medical