The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling
| Autor: | Lesley-Ann Martin, Ian Farmer, C Kimberley, S.R.D. Johnston, C. M. W Chan, Sunil Pancholi, Mitch Dowsett |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
medicine.medical_specialty Antineoplastic Agents Hormonal Transcription Genetic Endocrinology Diabetes and Metabolism Down-Regulation Apoptosis Breast Neoplasms Receptor IGF Type 1 Insulin Antagonists Endocrinology Downregulation and upregulation Internal medicine polycyclic compounds medicine Estrogen Receptor beta Humans Insulin Growth factor receptor inhibitor skin and connective tissue diseases Fulvestrant Estrogen receptor beta Cell Proliferation Estradiol Chemistry Estrogen Antagonists Estrogen Receptor alpha Intracellular Signaling Peptides and Proteins Estrogens Phosphoproteins IRS2 Tamoxifen Oncology MCF-7 Insulin Receptor Substrate Proteins Female Estrogen receptor alpha hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Endocrine-related cancer. 12(4) |
| ISSN: | 1351-0088 |
| Popis: | Long-term culture of MCF-7 wild-type (wt) cells in steroid-depleted medium (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of ERalpha and enhanced growth factor signalling. In this study, we aimed to compare the effects of the pure anti-oestrogen ICI 182,780 (ICI) with the competitive anti-oestrogen tamoxifen (TAM) on oestrogen and IGF signalling in these cells. Wt MCF-7 and LTED cells were treated with a log 7 concentration range of E2, TAM or ICI. Effects on cell growth, ERalpha transactivation, expression of ERalpha, ERbeta and components of the IGF pathway were measured with and without insulin. In the presence of insulin, growth of LTED cells was refractory to TAM but inhibited by ICI and E2. In the absence of insulin, LTED cells showed persistent hypersensitivity to E2, and remained inhibited by ICI but were largely unaffected by TAM. ICI but not TAM inhibited ER-mediated gene transcription and treatment with ICI resulted in a dose-dependent reduction in ERalpha levels whilst having no effect on ERbeta expression. IGF-I receptor and insulin receptor substrate 2 levels were increased in LTED versus the Wt MCF-7 cells, and ICI but not TAM reduced their expression in a dose-dependent fashion. Thus IGF signalling as well as ERalpha expression and function are enhanced during LTED. While the resultant cells are resistant to TAM, ICI down-regulates ERalpha, reducing IGF signalling and cell growth. These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor. |
| Databáze: | OpenAIRE |
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