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Institute of Cancer Research, The Breakthrough Breast Cancer Research Centre, 237 Fulham Road, London SW3 6JB, UK¹ Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark² Department of Medicine, Royal Marsden Hospital, Fulham Road, London, UK

(Correspondence should be addressed to L-A Martin; Email: lesley-ann.martin{at}icr.ac.uk)

Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line (Tam^R-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that Tam^R-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 Tam^R-1 cells had increased phosphorylation of ESR1 ser¹⁶⁷. SiRNA blockade of AKT or MAPK3/1 had little effect on ESR1 ser¹⁶⁷ phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ESR1 in the Tam^R-1 but not MCF-7 cells. ESR1 was redistributed to extranuclear sites in Tam^R-1 and was less transcriptionally competent compared with MCF-7 suggesting that nuclear ESR1 activity was suppressed in Tam^R-1. Tamoxifen resistance in the Tam^R-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.

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