Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1
Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1
复制标题
小分子二甲苯茚素 G 通过诱导 GABARAPL1 触发从基底型乳腺癌亚型转变为管腔型乳腺癌亚型。
DOI：
10.1038/s41419-020-02878-z
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发表时间：
2020-08-15
影响因子：
9
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Fan, Minmin;Chen, Jingwei;Xu, Qiang
乳腺癌是一种异质性疾病，包括不同的分子亚型。基底样亚型预后差，复发率高，而管腔样亚型患者预后更好，部分原因是抗激素治疗反应性。在这里，我们证明，二氢吲哚甘油醚G（Dip G），一种天然产物，在基底样乳腺癌细胞系和动物模型中表现出强大的分化诱导活性。具体而言，Dip G治疗导致部分转录组从基底转移到管腔基因表达特征，并促使基底样乳腺肿瘤对他莫昔芬治疗敏感。Dip G上调GABARAPL 1（GABA（A）受体相关蛋白样1）和ER β的表达。我们揭示了GABARAPL 1作为依赖于ER β水平的乳腺癌亚型特异性调节剂的一个先前未被认识的作用。我们的研究结果揭示了通过表型转换治疗基底细胞样乳腺癌的新机会，并表明Dip G可作为治疗基底细胞样乳腺癌的主要化合物。
Breast cancer is a heterogeneous disease that includes different molecular subtypes. The basal-like subtype has a poor prognosis and a high recurrence rate, whereas the luminal-like subtype confers a more favorable patient prognosis partially due to anti-hormone therapy responsiveness. Here, we demonstrate that diptoindonesin G (Dip G), a natural product, exhibits robust differentiation-inducing activity in basal-like breast cancer cell lines and animal models. Specifically, Dip G treatment caused a partial transcriptome shift from basal to luminal gene expression signatures and prompted sensitization of basal-like breast tumors to tamoxifen therapy. Dip G upregulated the expression of both GABARAPL1 (GABA(A) receptor-associated protein-like 1) and ER beta. We revealed a previously unappreciated role of GABARAPL1 as a regulator in the specification of breast cancer subtypes that is dependent on ER beta levels. Our findings shed light on new therapeutic opportunities for basal-like breast cancer via a phenotype switch and indicate that Dip G may serve as a leading compound for the therapy of basal-like breast cancer.