Abstract
Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERβ) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERβ under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERβ in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERβ of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERβ association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERβ association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERβ in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.
Highlights
Breast cancer (BC) is one of the most common malignancies in women, accounting for about 25% of all new cancer cases and representing the leading cause of cancer death in women
We investigated here the effects of Estrogen Receptor β (ERβ) in triplenegative breast cancer (TNBC) cells by combining interactional proteomics and genomics, in order to functionally elucidate the molecular mechanism of receptor action
Characterization of the gene expression changes induced by ERβ led to the identification of genes whose expression is greatly influenced by the receptor in TNBC cells, including several genes known to be critical in TNBC biology, such as IGFBP3, ID1, NRP2, MAPK12, KCNN1, TM4SF1, TSPO, and ABAT, all of which result to be downregulated by the receptor
Summary
Breast cancer (BC) is one of the most common malignancies in women, accounting for about 25% of all new cancer cases and representing the leading cause of cancer death in women. Interactional proteomics, performed to unveil the molecular bases of ERβ action, revealed its nuclear association with protein complexes involved in several key biological events, such as DNA replication, transcription regulation, post-transcriptional mRNA expression, and small molecule biochemistry control. Multiple complexes, such as Polycomb Repressor Complexes 1 and 2, known to be involved in negative epigenetic regulation of transcription by chromatin remodelling, were found to be a part of ERβ interactome. These data allow us to suggest an immediate contribution of ERβ and its molecular partners in the downregulation of key pathways in TNBC, including those involved in cholesterol metabolism
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