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Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole
- Source :
- Cancer Research. 65:5380-5389
- Publication Year :
- 2005
- Publisher :
- American Association for Cancer Research (AACR), 2005.
-
Abstract
- Ovariectomized mice bearing tumor xenografts grown from aromatase-transfected estrogen receptor (ER)–positive human breast cancer cells (MCF-7Ca) were injected s.c. with 10 μg/d letrozole for up to 56 weeks. Western blot analysis of the tumors revealed that ERs (ERα) were increased at 4 weeks but decreased at weeks 28 and 56. Expression of erbB-2 and p-Shc increased throughout treatment, whereas growth factor receptor binding protein 2 (Grb2) increased only in tumors proliferating on letrozole (weeks 28 and 56). In cells isolated from tumors after 56 weeks and maintained as a cell line (LTLT-Ca) in 1 μmol/L letrozole, ERα was also decreased whereas erbB-2, adapter proteins (p-Shc and Grb2), and the signaling proteins in the mitogen-activated protein kinase (MAPK) cascade were increased compared with MCF-7Ca cells. Growth was inhibited in LTLT-Ca cells but not in MCF-7Ca cells treated with MAPK kinase 1/2 inhibitors U0126, and PD98059 (IC50 ∼25 μmol/L). PD98059 (5 μmol/L) also reduced MAPK activity and increased ERα to the levels in MCF-7Ca cells. Epidermal growth factor receptor kinase inhibitor, gefitinib (ZD1839) inhibited growth of LTLT-Ca cells (IC50 ∼10 μmol/L) and restored their sensitivity to tamoxifen and anastrozole. In xenografts, combined treatment with ER down-regulator fulvestrant and letrozole, prevented increases in erbB-2 and activation of MAPK and was highly effective in inhibiting tumor growth throughout 29 weeks of treatment. These results indicate that blocking both ER- and growth factor–mediated transcription resulted in the most effective inhibition of growth of ER-positive breast cancer cells.
- Subjects :
- MAPK/ERK pathway
Cancer Research
medicine.medical_specialty
MAP Kinase Signaling System
medicine.drug_class
Mice, Nude
Estrogen receptor
Breast Neoplasms
Biology
Drug Administration Schedule
Mice
Growth factor receptor binding
Cell Line, Tumor
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Nitriles
medicine
Animals
Humans
Protein kinase A
Mice, Inbred BALB C
Aromatase inhibitor
Fulvestrant
Aromatase Inhibitors
Letrozole
Estrogen Receptor alpha
Triazoles
Xenograft Model Antitumor Assays
Enzyme Activation
Tamoxifen
Endocrinology
Oncology
Cancer cell
Female
Mitogen-Activated Protein Kinases
medicine.drug
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 65
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....90740b8925c67a8d8b9356884a6d62ec