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.

中文翻译：

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腔内乳腺癌细胞中MKL1的核蓄积会损害ERα的基因组活性，并与内分泌抗性有关。

雌激素受体（ERα）在驱动激素依赖性乳腺癌的发展中起着核心作用。治疗这些癌症的主要挑战是了解和克服内分泌抵抗力。巨核细胞白血病1（MKL1，MRTFA）蛋白是肌动蛋白动态和细胞运动功能的主要调节剂，其核易位有利于上皮-间质转化。我们先前证明，在雌激素反应性乳腺癌细胞系中MKL1的核积累促进了激素的逃逸。在本研究中，我们通过组织芯片分析确认了MKL1的核免疫染色与一组乳腺癌患者的内分泌抵抗力有关，并且我们使用细胞系模型来解释其下划线机制。我们通过基因表达微阵列分析表明，MKL1的核积累诱导去分化，导致混合的腔/基底表型，并抑制雌激素介导的基因表达控制。结合高通量测序（ChIP-Seq）的DNA染色质免疫沉淀显示，与大量ERα结合位点（ERBS）大量丧失相关的ERα病严重重组，通常与较低的ERα结合水平有关。新型ERBS似乎与EGF和RAS信号通路有关。总的来说，这些结果突出了MKL1在某些内分泌抵抗性病例中观察到的ERα转录活性丧失中的主要作用，从而导致了乳腺癌细胞的恶性肿瘤。