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Published online July 21, 2008
doi:10.1083/jcb.200712125
The Journal of Cell Biology
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Lombardi et al.
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ARTICLE

 Hormone-dependent nuclear export of estradiol receptor and DNA synthesis in breast cancer cells

Maria Lombardi1, Gabriella Castoria1, Antimo Migliaccio1, Maria Vittoria Barone2, Rosina Di Stasio1, Alessandra Ciociola1, Daniela Bottero1, Hiroshi Yamaguchi3, Ettore Appella3, and Ferdinando Auricchio1

1 Dipartimento di Patologia Generale, Il Università di Napoli, 80138 Naples, Italy
2 European Laboratory for Food Induced Disease, Dipartimento di Pediatria, Università "Federico II," 80131 Naples, Italy
3 Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Correspondence to A. Migliaccio: antimo.migliaccio{at}unina2.it

In breast cancer cells, cytoplasmic localization of the estradiol receptor {alpha} (ER{alpha}) regulates estradiol-dependent S phase entry. We identified a nuclear export sequence (NES) in ER{alpha} and show that its export is dependent on both estradiol-mediated phosphatidylinositol-3-kinase (PI3K)/AKT activation and chromosome region maintenance 1 (CRM1). A Tat peptide containing the ER{alpha} NES disrupts ER{alpha}–CRM1 interaction and prevents nuclear export of ER{alpha}- and estradiol-induced DNA synthesis. NES-ER{alpha} mutants do not exit the nucleus and inhibit estradiol-induced S phase entry; ER{alpha}-dependent transcription is normal. ER{alpha} is associated with Forkhead proteins in the nucleus, and estradiol stimulates nuclear exit of both proteins. ER{alpha} knockdown or ER{alpha} NES mutations prevent ER{alpha} and Forkhead nuclear export. A mutant of forkhead in rhabdomyosarcoma (FKHR), which cannot be phosphorylated by estradiol-activated AKT, does not associate with ER{alpha} and is trapped in the nucleus, blocking S phase entry. In conclusion, estradiol-induced AKT-dependent phosphorylation of FKHR drives its association with ER{alpha}, thereby triggering complex export from the nucleus necessary for initiation of DNA synthesis and S phase entry.

M. Lombardi and G. Castoria contributed equally to this paper.

Abbreviations used in this paper: AR, androgen receptor; CRM1, chromosome region maintenance 1; ER, estradiol receptor; FKHR, forkhead in rhabdomyosarcoma; LMB, leptomycin B; NES, nuclear export signal; PgR, progesterone receptor; PI3K, phosphatidylinositol-3-kinase; wt, wild type.


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