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Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy

Oncogene volume 34, pages 1919–1927 (2015)Cite this article

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A Correction to this article was published on 21 September 2018

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Abstract

To elucidate the molecular mechanisms of tamoxifen resistance in breast cancer, we performed gene array analyses and identified 366 genes with altered expression in four unique tamoxifen-resistant (TamR) cell lines vs the parental tamoxifen-sensitive MCF-7/S0.5 cell line. Most of these genes were functionally linked to cell proliferation, death and control of gene expression, and include FYN, PRKCA, ITPR1, DPYD, DACH1, LYN, GBP1 and PRLR. Treatment with FYN-specific small interfering RNA or a SRC family kinase inhibitor reduced cell growth of TamR cell lines while exerting no significant effect on MCF-7/S0.5 cells. Moreover, overexpression of FYN in parental tamoxifen-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to tamoxifen treatment, whereas knockdown of FYN in the FYN-overexpressing MCF-7/S0.5 cells restored sensitivity to tamoxifen, demonstrating growth- and survival-promoting function of FYN in MCF-7 cells. FYN knockdown in TamR cells led to reduced phosphorylation of 14-3-3 and Cdc25A, suggesting that FYN, by activation of important cell cycle-associated proteins, may overcome the anti-proliferative effects of tamoxifen. Evaluation of the subcellular localization of FYN in primary breast tumors from two cohorts of endocrine-treated ER+ breast cancer patients, one with advanced disease (N=47) and the other with early disease (N=76), showed that in the former, plasma membrane-associated FYN expression strongly correlated with longer progression-free survival (P<0.0002). Similarly, in early breast cancer patients, membrane-associated expression of FYN in the primary breast tumor was significantly associated with increased metastasis-free (P<0.04) and overall (P<0.004) survival independent of tumor size, grade or lymph node status. Our results indicate that FYN has an important role in tamoxifen resistance, and its subcellular localization in breast tumor cells may be an important novel biomarker of response to endocrine therapy in breast cancer.

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  • 21 September 2018

    Since the online publication of the above article, the authors have noted errors in subfigures 1c and 3b. Therefore, new images of the original immmunocytochemistry stainings have been obtained for Fig. 1c, and the Western blots for siRNA-mediated FYN knockdown in Fig. 3b were repeated. The amended versions of Figs. 1c and 3b are now provided.

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Acknowledgements

We thank Lisbet Mortensen and Ole Nielsen at the Department of Pathology, Odense University Hospital, for excellent technical assistance and MK Occhipinti-Bender for editorial assistance. This work was supported in part by the Danish Cancer Society, the Danish Cancer Research Foundation, the Danish Research Council, the Danish Strategic Research Council, A Race Against Breast Cancer, Sino-Danish Breast Cancer Research Centre, NanoCAN Lundbeck Center of Excellence, Region of Southern Denmark Research Foundation, Odense University Hospital Research Council and Danish Center for Translational Breast Cancer research.

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  1. Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark

    D Elias, H Vever, M F Gjerstorff & H J Ditzel

  2. Department of Pathology, Slagelse Hospital, Slagelse, Denmark

    A-V Lænkholm

  3. Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Copenhagen, Denmark

    C W Yde & A E Lykkesfeldt

  4. Department of Oncology, Odense University Hospital, Odense, Denmark

    H J Ditzel

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Elias, D., Vever, H., Lænkholm, AV. et al. Gene expression profiling identifies FYN as an important molecule in tamoxifen resistance and a predictor of early recurrence in patients treated with endocrine therapy. Oncogene 34, 1919–1927 (2015). https://doi.org/10.1038/onc.2014.138

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