Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 530, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2021.111282
Keywords
Breast cancer; Endocrine resistance; Estrogen receptor; MRTFA; P160 family coactivators; NCOR1; SMRT; PI3K; src
Categories
Funding
- University of Rennes 1
- Inserm
- CNRS
- Ligue Contre le Cancer
Ask authors/readers for more resources
Activation and nuclear accumulation of MRTFA in ER alpha positive breast cancer cells remodels both ER alpha location and functions by shifting its activity from nuclear genome regulation to extra-nuclear non-genomic signaling.
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 (ER alpha) positive breast cancers by initiating a partial transition from luminal to basal-like phenotype and impairing ER alpha 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-)ER alpha 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-ER alpha monomer/dimer ratio towards the monomeric state, leading to significant functional consequences on ER alpha activities. In particular, the association of Apo-ER alpha with chromatin is drastically decreased, and the remaining ER alpha binding sites are substantially less enriched in ERE motifs than in control conditions. Monitored by proximity Ligation Assay, ER alpha interactions with P160 family coactivators are partly impacted when MRTFA accumulates in the nucleus, and those with SMRT and NCOR1 corepressors are abolished. Finally, ER alpha 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 ER alpha positive breast cancer cells remodels both ER alpha location and functions by shifting its activity from nuclear genome regulation to extra-nuclear non-genomic signaling.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available