Nuclear translocation of MRTFA in MCF7 breast cancer cells shifts ERα nuclear/genomic to extra-nuclear/non genomic actions

Abstract

The Myocardin-related transcription factor A [MRTFA, also known as Megakaryoblastic Leukemia 1 (MKL1))] is a major actor in the epithelial to mesenchymal transition (EMT). We have previously shown that activation and nuclear accumulation of MRTFA mediate endocrine resistance of estrogen receptor alpha (ERα) positive breast cancers by initiating a partial transition from luminal to basal-like phenotype and impairing ERα cistrome and transcriptome. In the present study, we deepen our understanding of the mechanism by monitoring functional changes in the receptor's activity. We demonstrate that MRTFA nuclear accumulation down-regulates the expression of the unliganded (Apo-)ERα and causes a redistribution of the protein localization from its normal nuclear place to the entire cell volume. This phenomenon is accompanied by a shift in Apo-ERα monomer/dimer ratio towards the monomeric state, leading to significant functional consequences on ERα activities. In particular, the association of Apo-ERα with chromatin is drastically decreased, and the remaining ERα binding sites are substantially less enriched in ERE motifs than in control conditions. Monitored by proximity Ligation Assay, ERα interactions with P160 family coactivators are partly impacted when MRTFA accumulates in the nucleus, and those with SMRT and NCOR1 corepressors are abolished. Finally, ERα interactions with kinases such as c-src and PI3K are increased, thereby enhancing MAP Kinase and AKT activities. In conclusion, the activation and nuclear accumulation of MRTFA in ERα positive breast cancer cells remodels both ERα location and functions by shifting its activity from nuclear genome regulation to extra-nuclear non-genomic signaling.

miR-142-5p Inhibits Cell Invasion and Migration by Targeting DNMT1 in Breast Cancer

“…Studies have shown that MKL-1 inhibits cell proliferation and affects the G 1 –S phase of cell progression, resulting in cell growth arrest, and the expression of MKL-1 in tumor cells is significantly downregulated 25 . After MKL-1 was overexpressed or knocked out in two breast cancer cells, MDA-MB-231 and MCF-7, they were detected by Western blotting; the overexpression effect of MKL-1 in MDA-MB-231 and MCF-7 cells was significantly higher than that in the control group.…”

Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis

“…The induction of EMT–TFs and the acquisition of mesenchymal characteristics are associated with loss of ERα and resistance to antiestrogen therapies 13 , 38 , 39 , 74 , but the impact of early/hybrid states of EMT on ERα signaling had not been investigated. Here, we describe key roles for ZEB1 during early EMT stages in enhancing ERα responses and suggest that the functional ZEB1-ERα interaction may modulate the tissue tropism of breast cancer metastases.…”

Visualization of the protein–protein interactions of hormone receptors in hormone-dependent cancer research

“…The results showed that activation and nuclear accumulation of MRTFA in ERα-positive breast cancer cells shifts ERα nuclear/genomic action to extranuclear/nongenomic action (Jehanno et al, 2021). They revealed the interactions between endogenous ERα and IFI27/ISG12 in the cytoplasm, nucleus and perinuclear region in breast cancer cell MCF-7, T47D, and ZR-75-1 cells.…”