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Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor α and its phosphorylation at serine 305

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Abstract

Estrogens play a crucial role in breast tumor growth, which is the rationale for the use of antiestrogens, such as tamoxifen, in women with estrogen receptor (ER)-α-positive breast cancer. However, hormone resistance is a major clinical problem. Altered growth factor signaling to the ERα pathway has been shown to be associated with the development of clinical resistance. We previously have identified a mutation that replaces arginine for lysine at residue 303 (K303R) of ERα, which confers hypersensitive growth in low levels of estrogen. To determine if the K303R mutation could participate in the evolution of hormone resistance, we generated MCF-7 breast cancer cells stably transfected with either wild-type (WT) or K303R ERα. We found that the mutation confers decreased sensitivity to tamoxifen in the presence of the growth factor heregulin, using anchorage-independent growth assays. K303R ERα-expressing cells were hypersensitive to growth factor signals. Our data suggest that phosphorylation of serine 305 within the hinge domain of ERα might play a key role in increasing ligand-independent activity of the mutant receptor. We hypothesize that the mutation adapts the receptor for enhanced bidirectional cross-talk with the HER2 growth factor receptor pathway, which then impacts on responsiveness to tamoxifen.

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Acknowledgments

The authors would like to thank A. Beyer for expert technical assistance, and R. Sample for administrative assistance. This work was supported by NIH/NCI CA72038 to SAWF, and by an AIRC grant 2007 to CG.

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Authors and Affiliations

  1. Department of Pharmaco-Biology, University of Calabria, Rende, Italy

    Cinzia Giordano & Ines Barone

  2. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, MS: 600, N1200 Alkek, Houston, TX, 77030, USA

    Cinzia Giordano, Yukun Cui & Suzanne A. W. Fuqua

  3. Centro Sanitario and Department of Cellular Biology, University of Calabria, Arcavacata di Rende, 87036, Cosenza, Italy

    Sebastiano Ando

  4. Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Michael A. Mancini & Valeria Berno

Authors
  1. Cinzia Giordano
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  2. Yukun Cui
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  3. Ines Barone
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  4. Sebastiano Ando
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  5. Michael A. Mancini
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  6. Valeria Berno
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  7. Suzanne A. W. Fuqua
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Corresponding author

Correspondence to Suzanne A. W. Fuqua.

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Giordano, C., Cui, Y., Barone, I. et al. Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor α and its phosphorylation at serine 305. Breast Cancer Res Treat 119, 71–85 (2010). https://doi.org/10.1007/s10549-009-0334-0

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  • DOI: https://doi.org/10.1007/s10549-009-0334-0

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