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¹ CRUK Cancer Research Centre and Academic Breast Unit, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK,
² Department of Oncology, Georgetown University, Washington, District of Columbia, USA

(Requests for offprints should be addressed to S P Langdon; Email: simon.langdon{at}cancer.org.uk)

B Kuske and C Naughton contributed equally to this work.

Hormone-dependent estrogen receptor (ER)-positive breast cancer cells may adapt to low estrogen environments such as produced by aromatase inhibitors. In many instances, cells become insensitive to the effects of estrogen but may still retain dependence on ER. We have investigated the expression, function, and activation of ER in two endocrine-resistant MCF-7 models to identify mechanisms that could contribute to resistance. While MCF-7/LCC1 cells are partially estrogen dependent, MCF-7/LCC9 cells are fully estrogen insensitive and fulvestrant and tamoxifen resistant. In both MCF-7/LCC1 and MCF-7/LCC9 cell lines, high expression of ER was associated with enhanced binding to the trefoil factor 1 (TFF1) promoter in the absence of estrogen and increased transcription of TFF1 and progesterone receptor. In contrast to the observations derived from hypersensitive and supersensitive models, these cells were truly estrogen independent; nevertheless, removal of ER by siRNA, or fulvestrant, a specific ER downregulator, inhibited growth indicating dependence on ER. In the absence of estrogen, neither ER Ser¹¹⁸ nor Ser¹⁶⁷ were phosphorylated as frequently found in other ligand-independent cell line models. Addition of estrogen activated ER Ser¹¹⁸ in MCF-7 and LCC1 cells but not in LCC9 cells. We suggest that the estrogen-independent growth within these cell lines is accounted for by high levels of ER expression driving transcription and full estrogen independence explained by lack of ER activation through Ser¹¹⁸.

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