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Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells

Oncogene volume 31, pages 4868–4877 (2012)Cite this article

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Abstract

We report that in breast cancer cells, tyrosine phosphorylation of the estradiol receptor alpha (ERalpha) by Src regulates cytoplasmic localization of the receptor and DNA synthesis. Inhibition of Src or use of a peptide mimicking the ERalpha p-Tyr537 sequence abolishes ERalpha tyrosine phosphorylation and traps the receptor in nuclei of estradiol-treated MCF-7 cells. An ERalpha mutant carrying a mutation of Tyr537 to phenylalanine (ER537F) persistently localizes in nuclei of various cell types. In contrast with ERalpha wt, ER537F does not associate with Ran and its interaction with Crm1 is insensitive to estradiol. Thus, independently of estradiol, ER537F is retained in nuclei, where it entangles FKHR-driving cell cycle arrest. Chromatin immunoprecipitation analysis reveals that overexpression of ER537F in breast cancer cells enhances FKHR interaction with cyclin D1 promoter. This mutant also counteracts cell transformation by the activated forms of Src or PI3-K. In conclusion, in addition to regulating receptor localization, ERalpha phosphorylation by Src is required for hormone responsiveness of DNA synthesis in breast cancer cells.

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Acknowledgements

This work was funded by the Italian Association for Cancer Research (A.I.R.C.; Grant No. IG 5389). PG is supported by a fellowship from A.I.R.C.

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Authors and Affiliations

  1. Department of General Pathology, II University of Naples, Naples, Italy

    G Castoria, P Giovannelli, M Lombardi, C De Rosa, T Giraldi, A de Falco, C Abbondanza, A Migliaccio & F Auricchio

  2. European Laboratory of Food Induced Disease (ELFID), Naples, Italy

    M V Barone

  3. These authors contributed equally to this work,

    G Castoria & P Giovannelli

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  1. G Castoria
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Correspondence to A Migliaccio.

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Castoria, G., Giovannelli, P., Lombardi, M. et al. Tyrosine phosphorylation of estradiol receptor by Src regulates its hormone-dependent nuclear export and cell cycle progression in breast cancer cells. Oncogene 31, 4868–4877 (2012). https://doi.org/10.1038/onc.2011.642

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