RUNX1可防止雌激素介导的雌激素受体阳性乳腺癌中AXIN1抑制和β-连环蛋白激活。

RUNX1 prevents oestrogen-mediated AXIN1 suppression and β-catenin activation in ER-positive breast cancer.

作者信息

Chimge Nyam-Osor, Little Gillian H, Baniwal Sanjeev K, Adisetiyo Helty, Xie Ying, Zhang Tian, O'Laughlin Andie, Liu Zhi Y, Ulrich Peaches, Martin Anthony, Mhawech-Fauceglia Paulette, Ellis Matthew J, Tripathy Debu, Groshen Susan, Liang Chengyu, Li Zhe, Schones Dustin E, Frenkel Baruch

机构信息

Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.

Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.

出版信息

Nat Commun. 2016 Feb 26;7:10751. doi: 10.1038/ncomms10751.

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.

近期的高通量研究揭示了乳腺癌中，尤其是雌激素受体阳性（ER(+)）肿瘤中存在反复出现的RUNX1突变。然而，RUNX1介导的肿瘤抑制潜在机制仍不清楚。在此，我们通过在体内和体外去除乳腺上皮细胞中的RUNX1，证明了RUNX1和雌激素对AXIN1的联合调控。RUNX1和雌激素受体占据AXIN1第二个内含子中的相邻元件，并且RUNX1拮抗雌激素介导的AXIN1抑制。相应地，RNA测序和免疫组织化学分析表明，在肿瘤活检中RUNX1和AXIN1之间存在雌激素依赖性关联。ER(+)乳腺上皮细胞中RUNX1的缺失会增加β-连环蛋白，使有丝分裂失调，并刺激细胞增殖和干细胞标志物的表达。然而，它不会刺激LEF/TCF、c-Myc或CCND1，也不会加速G1/S细胞周期阶段转变。最后, 在体外通过稳定AXIN1可改善RUNX1缺失介导的β-连环蛋白失调和有丝分裂，这突出了AXIN1作为ER(+)乳腺癌治疗潜在靶点的作用。