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High IGF-IR Activity in Triple-Negative Breast Cancer Cell Lines and Tumorgrafts Correlates with Sensitivity to Anti–IGF-IR Therapy
- Source :
- Clinical Cancer Research. 17:2314-2327
- Publication Year :
- 2011
- Publisher :
- American Association for Cancer Research (AACR), 2011.
-
Abstract
- Purpose: We previously reported an insulin-like growth factor (IGF) gene expression signature, based on genes induced or repressed by IGF-I, which correlated with poor prognosis in breast cancer. We tested whether the IGF signature was affected by anti–IGF-I receptor (IGF-IR) inhibitors and whether the IGF signature correlated with response to a dual anti–IGF-IR/insulin receptor (InsR) inhibitor, BMS-754807. Experimental Design: An IGF gene expression signature was examined in human breast tumors and cell lines and changes were noted following treatment of cell lines or xenografts with anti–IGF-IR antibodies or tyrosine kinase inhibitors. Sensitivity of cells to BMS-754807 was correlated with levels of the IGF signature. Human primary tumorgrafts were analyzed for the IGF signature and IGF-IR levels and activity, and MC1 tumorgrafts were treated with BMS-754807 and chemotherapy. Results: The IGF gene expression signature was reversed in three different models (cancer cell lines or xenografts) treated with three different anti–IGF-IR therapies. The IGF signature was present in triple-negative breast cancers (TNBC) and TNBC cell lines, which were especially sensitive to BMS-754807, and sensitivity was significantly correlated to the expression of the IGF gene signature. The TNBC primary human tumorgraft MC1 showed high levels of both expression and activity of IGF-IR and IGF gene signature score. Treatment of MC1 with BMS-754807 showed growth inhibition and, in combination with docetaxel, tumor regression occurred until no tumor was palpable. Regression was associated with reduced proliferation, increased apoptosis, and mitotic catastrophe. Conclusions: These studies provide a clear biological rationale to test anti–IGF-IR/InsR therapy in combination with chemotherapy in patients with TNBC. Clin Cancer Res; 17(8); 2314–27. ©2011 AACR.
- Subjects :
- Cancer Research
medicine.medical_specialty
Receptor, ErbB-2
Immunoblotting
Apoptosis
Breast Neoplasms
Docetaxel
Mice, SCID
Biology
Article
Receptor, IGF Type 1
Mice
Breast cancer
Mice, Inbred NOD
Cell Line, Tumor
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Cluster Analysis
Humans
Insulin-Like Growth Factor I
Triple-negative breast cancer
Cell Proliferation
Regulation of gene expression
Reverse Transcriptase Polymerase Chain Reaction
Triazines
Cell growth
Gene Expression Profiling
Cancer
Gene signature
medicine.disease
Xenograft Model Antitumor Assays
Receptor, Insulin
Gene Expression Regulation, Neoplastic
Gene expression profiling
Endocrinology
Receptors, Estrogen
Oncology
NIH 3T3 Cells
Cancer research
Pyrazoles
Taxoids
Breast disease
Receptors, Progesterone
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....15430e3f8f98860363513f4326e29dec