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Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate

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Abstract

Fibroblast growth factor receptor-1 (FGFR-1) is amplified in 10% of human breast cancers. The goal of this study was to test the correlation between FGFR-1 amplification and expression and sensitivity to brivanib, an FGFR-1 small molecule inhibitor, in breast cancer cell lines in vitro. Using CGH array and gene expression profiling, FGFR-1 DNA copy number, mRNA, and protein expression were measured in 21 cell lines and correlated with growth inhibition by brivanib. We examined FGFR-1 autophosphorylation and kinase activity, as well as phosphorylation of downstream signaling molecules in response to bFGF and brivanib exposure. CAMA, MDA-MB-361, and HCC38 cells had FGFR-1 amplification and protein overexpression. Brivanib GI50 values were significantly lower in the gene amplified (15.17 μM, n = 3) compared to normal copy number (69.09 μM, n = 11) or FGFR-1 deleted (76.14 μM, n = 7) cells (P = 0.0107). Among nonamplified cells, there was no correlation between FGFR-1 mRNA or protein expression levels and brivanib sensitivity. Two of three FGFR-1 amplified cells were sensitive to bFGF-induced growth stimulation, which was blocked by brivanib. In cells with amplified FGFR-1, brivanib decreased receptor autophosphorylation, inhibited bFGF-induced tyrosine kinase activity, and reduced phosphorylation of ERK and AKT. Breast cancer cell lines with FGFR-1 gene amplification and protein overexpression are more sensitive to growth inhibition by brivanib than nonamplified cells. These findings suggest that FGFR-1 amplification or protein overexpression in breast cancers may be an indicator for brivanib treatment, where it may have direct anti-proliferative effects in addition to its’ anti-angiogenic effects.

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Acknowledgments

Grant support was provided by the Breast Cancer Research Foundation (New York, NY; grant to L. Pusztai). We thank Mark Ayers of Bristol-Myers Squibb Company for providing brivanib alaninate.

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Authors and Affiliations

  1. Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Houston, TX, 77230-1439, USA

    Christine Y. Shiang, Bailiang Wang, Gabriel N. Hortobagyi & Lajos Pusztai

  2. Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Yuan Qi & Jing Wang

  3. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    W. Fraser Symmans

  4. Program in Human Biology and Patient-Based Research, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    Christine Y. Shiang & Lajos Pusztai

  5. Genomic Unit, Institut Gustave Roussy France, Villejuif, France

    Vladimir Lazar

  6. Department of Breast Cancer Translational Research Unit, UPRES EA03535, Université Paris XI, Institut Gustave Roussy France, Villejuif, France

    Fabrice Andre

Authors
  1. Christine Y. Shiang
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  2. Yuan Qi
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  3. Bailiang Wang
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  4. Vladimir Lazar
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  5. Jing Wang
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  6. W. Fraser Symmans
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  7. Gabriel N. Hortobagyi
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  8. Fabrice Andre
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  9. Lajos Pusztai
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Corresponding author

Correspondence to Lajos Pusztai.

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Supplementary Fig. 1

The baseline effects of brivanib on bFGF-induced proliferation. MDA-MB-361, CAMA-1, and MDA-MB-157 cells were stimulated by bFGF and 0.1, 1, or 10 μM brivanib inhibited this bFGF-induced growth in a dose-dependent manner. HCC38 cells were not sensitive to bFGF, but were inhibited by brivanib, whereas the FGFR-1 deleted AU565 and BT-474 cells were insensitive to both bFGF and brivanib. Percentage of cell viability relative to bFGF treatment alone is shown for bFGF and 0.1, 1, or 10 μM brivanib (PDF 26 kb)

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Shiang, C.Y., Qi, Y., Wang, B. et al. Amplification of fibroblast growth factor receptor-1 in breast cancer and the effects of brivanib alaninate. Breast Cancer Res Treat 123, 747–755 (2010). https://doi.org/10.1007/s10549-009-0677-6

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  • DOI: https://doi.org/10.1007/s10549-009-0677-6

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