BACKGROUND: The transcriptional activity of estrogen receptor �� (ER��) in breast cancer (BC) is extensively characterized. Our group has previously shown that ER�� controls the expression of a number of genes in its unliganded form (apoER��), among which a large group of RNA-binding proteins (RBPs) encode genes, suggesting its role in the control of co- and post-transcriptional events. METHODS: apoER��-mediated RNA processing events were characterized by the analysis of transcript usage and alternative splicing changes in an RNA-sequencing dataset from MCF-7 cells after siRNA-induced ER�� downregulation. RESULTS: ApoER�� depletion induced an expression change of 681 RBPs, including 84 splicing factors involved in translation, ribonucleoprotein complex assembly, and 3'end processing. ApoER�� depletion results in 758 isoform switching events with effects on 3'end length and the splicing of alternative cassette exons. The functional enrichment of these events shows that post-transcriptional regulation is part of the mechanisms by which apoER�� controls epithelial-to-mesenchymal transition and BC cell proliferation. In primary BCs, the inclusion levels of the experimentally identified alternatively spliced exons are associated with overall and disease-free survival. CONCLUSION: Our data supports the role of apoER�� in maintaining the luminal phenotype of BC cells by extensively regulating gene expression at the alternative splicing level.