ER splice variant expression in four large cohorts of human breast cancer patient tumors.
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abstract
Though the role of Estrogen Receptor (ER) in breast cancer has been studied extensively, there is little consensus about the role of alternative ER isoform ER in breast cancer biology. ER has significant sequence homology to ER but is located on a different chromosome and maintains both overlapping and unique functional attributes. Five variants exist, resulting from alternative splicing of the C-terminal region of ER. The relevance of ER variants in breast cancer outcomes and response to therapy is difficult to assess because of conflicting reports in the literature, likely due to variable methods used to assess ER in patient tumors. Here, we quantitatively assess expression of ER splice variants on over 2,000 breast cancer patient samples. Antibodies against ER variants were validated for staining specificity in cell lines by siRNA knockdown of ESR2 and staining reproducibility on formalin-fixed paraffin-embedded tissue by quantitative immunofluorescence (QIF) using AQUA technology. We found antibodies against splice variants ER1 and ER5, but not ER2/cx, which were sensitive, specific, and reproducible. QIF staining of validated antibodies showed both ER1 and ER5 QIF scores, which have a normal (bell shaped) distribution on most cohorts assessed, and their expression is significantly associated with each other. Extensive survival analyses show that ER1 is not a prognostic or predictive biomarker for breast cancer. ER5 appears to be a context-dependent marker of worse outcome in HER2-positive and triple-negative patients, suggesting an unknown biological function in the absence of ER.
