Differential effects of estradiol and its analogs on cyclin D1 and CDK4 expression in estrogen receptor positive MCF-7 and estrogen receptor-transfected MCF-10AEwt5 cells
| Autor: | Thekkumkat Thomas, E. J. Yurkow, Jiantao Hong, Thresia Thomas, Michael A. Gallo, Neha Shah |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Cancer Research
medicine.medical_specialty Time Factors medicine.drug_class Cyclin D Estrogen receptor Breast Neoplasms Transfection Cyclin D1 Internal medicine Proto-Oncogene Proteins medicine Tumor Cells Cultured Humans biology Estradiol Cyclin-dependent kinase 4 Cell growth Cell Cycle Cyclin-Dependent Kinase 4 General Medicine Cell cycle Cyclin-Dependent Kinases Recombinant Proteins Cell biology Kinetics Endocrinology Oncology Receptors Estrogen Estrogen biology.protein Female hormones hormone substitutes and hormone antagonists Cell Division |
| Zdroj: | Oncology reports. 5(5) |
| ISSN: | 1021-335X |
| Popis: | Estradiol stimulates the growth of a majority of human breast tumors containing the estrogen receptors (ERs), proteins that mediates estrogen function. Opposing effects of estradiol have been found in cells expressing endogenous ER and those containing a transfected ER. To understand the role of estradiol structure in diverse estrogenic responses related to cell cycle regulation, we evaluated the effects of estradiol and its analogs on cell cycle progression, and the expression of cyclin D1 and the cyclin dependent kinase 4 (CDK4) in ER-positive MCF-7 and ER-transfected MCF-10AE wt5 cells. Four analogs of estradiol, with a re-positioned or a deleted hydroxyl group, were used. Our results show that estradiol and all of the analogs facilitated cell cycle progression of MCF-7 cells. In contrast, only estradiol inhibited the cell cycle progression of MCF-10AE wt5 cells significantly. Western blot analysis revealed that cyclin D1 protein increased to the maximal level by 6 h after the initiation of cell cycle from G 1 phase of MCF-7 cells. The least effective analog in inducing cyclin D1 was 3-hydroxyestratriene. However, this analog was most effective at inducing CDK4, contributing to its efficacy in facilitating MCF-7 cell cycle. In contrast to MCF-7 cells, the level of cyclin D1 protein was not influenced significantly by estradiol or its analogs in MCF-10AE wt5 cells. Sucrose gradient sedimentation analysis of ER from MCF-7 cells showed that the major peak of [ 3 H]-estradiol bound to ER could be displaced by a 10-fold excess of unlabelled estradiol or any of the analogs. In contrast, several analogs were less effective than unlabelled estradiol in competitive displacement of [ 3 H]-estradiol bound to ER from MCF-10AE wt5 cells. These data indicate that the induction of cyclin D1 is an important part of the growth stimulatory effects of estrogens in MCF-7 cells, but it may not be involved in growth inhibition of MCF-10AE wt5 cells. Our results also show that estrogenic compounds interact with ER from MCF-10AE wt5 cells with altered ligand binding affinity, possibly due to the absence or dysfunction of certain transcription factors or ER-associated proteins that co-regulate ER function. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|