Endocrine therapy resistance can be associated with high estrogen receptor α (ERα) expression and reduced ERα phosphorylation in breast cancer models

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 alpha 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-7/1-CC11 and MCF-7/LCC9 cell lines, high expression of ERa 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 alpha by siRNA, or fulvestrant, a specific ER downregulator, inhibited growth indicating dependence on ERa. In the absence of estrogen, neither ER alpha Ser(118) nor Ser(167) were phosphorylated as frequently found in other ligandin-dependent cell line models. Addition of estrogen activated ER alpha Ser(118) 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 ERa expression driving transcription and full estrogen independence explained by lack of ER alpha activation through Ser(118).