Recent high-throughput studies revealed recurrent RUNX1 mutations in breast cancer, specifically in oestrogen receptor-positive (ER(+)) tumours. However, mechanisms underlying the implied RUNX1-mediated tumour suppression remain elusive. Here, by depleting mammary epithelial cells of RUNX1 in vivo and in vitro, we demonstrate combinatorial regulation of AXIN1 by RUNX1 and oestrogen. RUNX1 and ER occupy adjacent elements in AXIN1's second intron, and RUNX1 antagonizes oestrogen-mediated AXIN1 suppression. Accordingly, RNA-seq and immunohistochemical analyses demonstrate an ER-dependent correlation between RUNX1 and AXIN1 in tumour biopsies. RUNX1 loss in ER(+) mammary epithelial cells increases β-catenin, deregulates mitosis and stimulates cell proliferation and expression of stem cell markers. However, it does not stimulate LEF/TCF, c-Myc or CCND1, and it does not accelerate G1/S cell cycle phase transition. Finally, RUNX1 loss-mediated deregulation of β-catenin and mitosis is ameliorated by AXIN1 stabilization in vitro, highlighting AXIN1 as a potential target for the management of ER(+) breast cancer.

中文翻译：

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RUNX1可以防止雌激素介导的AXIN1抑制和ER阳性乳腺癌中的β-catenin活化。

最近的高通量研究显示乳腺癌，特别是在雌激素受体阳性（ER（+））肿瘤中复发性RUNX1突变。但是，隐含的RUNX1介导的肿瘤抑制的潜在机制仍然难以捉摸。在这里，通过体内和体外消耗RUNX1的乳腺上皮细胞，我们证明了RUNX1和雌激素对AXIN1的组合调节。RUNX1和ER占据AXIN1第二个内含子中的相邻元素，而RUNX1拮抗雌激素介导的AXIN1抑制作用。因此，RNA-seq和免疫组织化学分析表明在肿瘤活检中RUNX1和AXIN1之间存在ER依赖性相关性。ER（+）乳腺上皮细胞中RUNX1的丢失增加了β-catenin，调节了有丝分裂，并刺激了细胞增殖和干细胞标志物的表达。但是，它不会刺激LEF / TCF，c-Myc或CCND1，它不会加速G1 / S细胞周期的相变。最后，通过AXIN1体外稳定作用可改善RUNX1介导的β-catenin和有丝分裂失控，这突出了AXIN1作为治疗ER（+）乳腺癌的潜在目标。