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Endocrine-Related Cancer 15 (4) 985-1002    DOI: 10.1677/ERC-07-0240
Copyright © 2008 by the Society for Endocrinology.
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ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2

 Sunil Pancholi, Anne E Lykkesfeldt1, Caroline Hilmi, Susana Banerjee, Alexandra Leary, Suzanne Drury, Stephen Johnston 2, Mitch Dowsett and Lesley-Ann Martin

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 (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 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 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.






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