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1 Molecular Endocrinology, Breakthrough Breast Cancer Centre, Institute of Cancer Research, Chester Beatty Laboratories, Fulham Rd, London SW3 6JB, UK
2 Breast Unit, Royal Marsden Hospital, Fulham Rd, London SW3 6JJ, UK
3 Department of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK
4 Academic Department of Biochemistry, Institute of Cancer Research, Royal Marsden Hospital, Fulham Rd, London, SW3 6JJ, UK
(Requests for offprints should be addressed to Lesley-Anne Martin; Email: lesley-ann.martin{at}icr.ac.uk)
This paper was presented at the 1st Tenovus/AstraZeneca Workshop, Cardiff (2005). AstraZeneca has supported the publication of these proceedings.
The knowledge that steroids play a pivotal role in the development of breast cancer has been exploited clinically by the development of endocrine treatments. These have sought to perturb the steroid hormone environment of the tumour cells, predominately by withdrawal or antagonism of oestrogen. Unfortunately, the beneficial actions of existing endocrine treatments are attenuated by the ability of tumours to circumvent the need for steroid hormones, whilst in most cases, retaining the nuclear steroid receptors. The mechanisms involved in resistance to estrogen deprivation are of major clinical relevance for optimal treatment of breast cancer patients and the development of new therapeutic regimes. We have shown that long-term culture of MCF7 cells in medium depleted of oestrogen (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of both ER
phosphorylated on Ser118 and ERK1/ERK2. Our data suggest elevated ERK1/ERK2 activity results wholly or in part from enhanced ERBB2 expression in the LTED cells. These cells showed greater sensitivity to the tyrosine kinase inhibitor ZD1839 in both ER-mediated transcription and growth assays compared with the wt-MCF7. Similarly the MEK inhibitor U0126 decreased basal ER-mediated transcription and proliferation in the LTED cells by 50% and reduced their sensitivity to the proliferative effects of E2 10-fold, whilst having no effect on the wild type (wt). However, complete suppression of ERK1/ERK2 activity in the LTED cells did not inhibit ER Ser118 phosphorylation suggesting that the cells remained ligand-dependent. This was further confirmed by the increased sensitivity of the LTED cells to the growth suppressive effects of ICI 182,780 and suggested that the LTED cells remained wholly or partially dependent on oestrogen receptor (ER)/oestrogen responsive elements directed growth. These findings suggest that treatments targeted at growth factor signalling pathways may be useful in patients acquiring resistance to oestrogen deprivation with aromatase inhibitors and that the pure anti-oestrogen ICI 182,780 may also be effective by blocking or destabilizing ER and hence disrupting cross-talk.
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  J.-M. Renoir, C. Bouclier, A. Seguin, V. Marsaud, and B. Sola Antioestrogen-mediated cell cycle arrest and apoptosis induction in breast cancer and multiple myeloma cells J. Mol. Endocrinol., March 1, 2008; 40(3): 101 - 112. [Abstract] [Full Text] [PDF]
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 B. Kuske, C. Naughton, K. Moore, K. G MacLeod, W. R Miller, R. Clarke, S. P Langdon, and D. A Cameron Endocrine therapy resistance can be associated with high estrogen receptor {alpha} (ER{alpha}) expression and reduced ER{alpha} phosphorylation in breast cancer models Endocr. Relat. Cancer, December 1, 2006; 13(4): 1121 - 1133. [Abstract] [Full Text] [PDF]
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J M W Gee, A Howell, W J Gullick, C C Benz, R L Sutherland, R J Santen, L-A Martin, F Ciardiello, W R Miller, M Dowsett, et al. Consensus Statement Endocr. Relat. Cancer, July 1, 2005; 12(Supplement_1): S1 - S7. [Abstract] [Full Text] [PDF]
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