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S Pancholi, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom
A Lykkesfeldt, Danish Cancer Society, Copenhagen, Denmark
C Hilmi, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom
S Banerjee, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom
A Leary, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom
S Drury, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom
S Johnston, Medicine, Royal Marsden Hospital, London, United Kingdom
M Dowsett, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom
L Martin, Institute of Cancer Research, Breakthrough Breast Cancer Centre, London, United Kingdom

Correspondence: Lesley-Ann Martin, Email: Lesley-Ann.Martin{at}icr.ac.uk

Abstract

Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumours. We used an MCF-7 breast tumour cell line (TamR-1) resistant to tamoxifen to investigate this mechanism. We demonstrate that TamR-1 express elevated levels of phosphorylated AKT and ERK1/2-activated p90RSK compared to the parental MCF-7 cell line (MCF-7). There was no change in the level of total ER alpha between the two cell lines, however the TamR-1 cells had increased phosphorylation of ER alpha ser167. siRNA blockade of AKT or ERK1/2 had little effect on ER alpha ser167 phosphorylation, but a combination of the two siRNAs abrogated this. Co-localization studies revealed an association between ERBB2 and ER alpha in the TamR-1 but not MCF-7 cells. ER alpha was redistributed to extra-nuclear sites in TamR-1 and was less transcriptionally competent compared to MCF-7 suggesting nuclear ER alpha 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 ER alpha to the nucleus. These data demonstrate that tamoxifen resistant cells have the ability to switch between ERBB2 or ER pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.

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