Transition of breast cancer cells from luminal to basal-like phenotype engages a shift from genomic to non-genomic activities of ERα activity

ABSTRACT: Estrogen receptor (ERα) is central in driving the development of hormone-dependent breast cancers. A major challenge in treating these cancers is to understand and struggle endocrine resistance. We have previously shown that the Megakaryoblastic Leukemia 1 (MKL1) protein, a master regulator of actin dynamic and cellular motile functions, directs down-regulation of ERα and hormonal escape of estrogen-responsive breast cancer cell lines. In the present study, we decipher the underlining mechanisms by tracking functional changes in ERα activity. We demonstrate through gene expression microarray analysis that the constitutive activation of MKL1 in ERα-positive MCF7 breast cancer cells induces a transition from a luminal to a basal-like phenotype and suppresses almost all regulations of gene expression by estrogen. Chromatin immunoprecipitation of DNA coupled to high-throughput sequencing (ChIP-Seq) shows a profound reprogramming in ERα cistrome associated with a massive loss of ERα binding sites (ERBSs) generally associated with lower ERα-binding activity. Novel ERBSs appear to be associated with EGF and RAS signaling pathways. ERα dynamic was further impacted by a displacement of its monomer/dimer equilibrium towards its monomer state, associated with a redistribution of the normally nuclear ERα protein to the entire cell volume. We next show that the combination of these remodeled dynamics of ERα alters its interactions with genomic and non-genomic partners. In particular, the formation of ERα/kinase complexes was promoted by the constitutive activation of MKL1. Hence, MKL1-induced transition of ER-positive breast cancer cells from luminal to basal-like phenotype shifts ERα activities from genomic to non-genomic function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107924 | GEO | 2019/09/11

SECONDARY ACCESSION(S): PRJNA421941

REPOSITORIES: GEO