Nuclear accumulation of MKL1 in luminal breast cancer cells impairs genomic activity of ERα and is associated with endocrine resistance

Charly Jehanno (1, 2) , Tamara Fernández-Calero (3, 4, 5) , Denis Habauzit (1) , Stéphane Avner (6) , Frédéric Percevault (1) , Emmanuelle Jullion (6) , Pascale Le Goff (1) , Marie May Coissieux (2) , Simone Muenst (2) , Mónica Marín (4) , Denis Michel (1) , Raphaël Metivier (6) , Gilles Flouriot (1)

1 Irset - Institut de recherche en santé, environnement et travail
2 University Hospital Basel [Basel]
3 Institut Pasteur de Montevideo
4 UDELAR - Universidad de la República [Montevideo]
5 UCU - Universidad Católica del Uruguay [Montevideo, Uruguay]
6 IGDR - Institut de Génétique et Développement de Rennes

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 overcome endocrine resistance. The Megakaryoblastic Leukemia 1 (MKL1, MRTFA) protein is a master regulator of actin dynamic and cellular motile functions, whose nuclear translocation favors epithelial-mesenchymal transition. We previously demonstrated that nuclear accumulation of MKL1 in estrogen-responsive breast cancer cell lines promotes hormonal escape. In the present study, we confirm through tissue microarray analysis that nuclear immunostaining of MKL1 is associated with endocrine resistance in a cohort of breast cancers and we decipher the underlining mechanisms using cell line models. We show through gene expression microarray analysis that the nuclear accumulation of MKL1 induces dedifferentiation leading to a mixed luminal/basal phenotype and suppresses estrogen-mediated control of gene expression. 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 levels. Novel ERBSs appear to be associated with EGF and RAS signaling pathways. Collectively, these results highlight a major role of MKL1 in the loss of ERα transcriptional activity observed in certain cases of endocrine resistances, thereby contributing to breast tumor cells malignancy.

Keywords: Breast cancer; Cistrome; Endocrine resistance; Estrogen receptor; Gene regulation; MKL1; Cistrome Journal Pre-proof

Domains: Life Sciences [q-bio]

Charly Jehanno, Tamara Fernández-Calero, Denis Habauzit, Stéphane Avner, Frédéric Percevault, et al.. Nuclear accumulation of MKL1 in luminal breast cancer cells impairs genomic activity of ERα and is associated with endocrine resistance. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms , 2020, 1863 (5), pp.194507. ⟨10.1016/j.bbagrm.2020.194507⟩. ⟨hal-02565572⟩