Résumé
Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line(TaMR-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that TaMR-1 express elevated levels of phosphorylated AKT and MAPK3/1 -activated RPS6KA2 compared with the parental MCF-7 cell line (MCF-7). There was no change in the level of total ESR between the two cell lines; however, the TaMR-1 cells had increased phosphorylation of ESR1 ser167. SiRNA blockade of AKTor MAPK3/1 had little effect on ESR1 ser phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ESR1 in the TaMR-1 but not MCF-7 cells. ESR1 was redistributed to extranuclear sites in TaMR-1 and was less transcriptionally competent compared with MCF-7 suggesting that nuclear ESR1 activity was suppressed in TaMR-1. Tamoxifen resistance in the TaMR-1 cells could be partially overcome by the ERBB2 inhibitor AG825 in combination with tamoxifen, and this was associated with re-localization of ESR1 to the nucleus. These data demonstrate that tamoxifen-resistant cells have the ability to switch between ERBB2 or ESR1 pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.
langue originale | Anglais |
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Pages (de - à) | 985-1002 |
Nombre de pages | 18 |
journal | Endocrine-Related Cancer |
Volume | 15 |
Numéro de publication | 4 |
Les DOIs | |
état | Publié - 1 déc. 2008 |
Modification externe | Oui |