Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer
Downregulation of miR-223 Expression Is an Early Event during Mammary Transformation and Confers Resistance to CDK4/6 Inhibitors in Luminal Breast Cancer
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DOI：
10.1158/0008-5472.can-19-1793
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发表时间：
2020-03-01
期刊：
影响因子：
11.2
通讯作者：
Belletti, Barbara
中科院分区：
文献类型：
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作者：
Citron, Francesca;Segatto, Ilenia;Belletti, Barbara
miR-223是一种抗炎miRNA，在癌症中以上下文依赖的方式作为癌抑制因子或癌启动子。在乳腺癌中，我们证明了它抑制了EGF通路的激活。然而，人们对miR-223在乳腺癌发生和发展中的作用知之甚少。miR-223在luminal亚型和HER2亚型乳腺癌中表达降低，且与患者预后呈负相关。在正常乳腺上皮细胞中，miR-223在三维环境下自主控制细胞的生长和形态。在MMTV-Delta 16HER2转基因小鼠模型中，癌基因转化导致miR-223的表达及时消失，可能是由于激活了已知的miR-223转录抑制因子E2F1。因此，使用CDK4/6抑制剂治疗，最终导致抑制E2F1活性，恢复miR-223的表达，miR-223消融诱导腔内乳腺癌对CDK4/6抑制的抵抗，无论是在体外还是在体内。值得注意的是，miR-223在管腔癌和her2阳性乳腺癌患者的微解剖导管原位癌（DCIS）中表达缺失。总之，这些结果确定miR-223下调是腔内乳腺癌发病的早期步骤，并表明它可用于识别侵袭性DCIS并预测对靶向治疗的反应。意义：miR-223可能是对CDK4/6抑制剂反应的预测性生物标志物，其缺失可以识别可能进展为浸润性乳腺癌的DCIS病变。
miR-223 is an anti-inflammatory miRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer, we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during breast cancer onset and progression. miR-223 expression was decreased in breast cancer of luminal and HER2 subtypes and inversely correlated with patients' prognosis. In normal luminal mammary epithelial cells, miR-223 acted cell autonomously in the control of their growth and morphology in three-dimensional context. In the MMTV-Delta 16HER2 transgenic mouse model, oncogene transformation resulted in a timely abrogation of miR-223 expression, likely due to activation of E2F1, a known repressor of miR-223 transcription. Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraining E2F1 activity, restored miR-223 expression and miR-223 ablation induced luminal breast cancer resistance to CDK4/6 inhibition, both in vitro and in vivo. Notably, miR-223 expression was lost in microdissected ductal carcinoma in situ (DCIS) from patients with luminal and HER2-positive breast cancer. Altogether, these results identify downmodulation of miR-223 as an early step in luminal breast cancer onset and suggest that it could be used to identify aggressive DCIS and predict the response to targeted therapy.Significance: miR-223 may represent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesions that are likely to progress into invasive breast cancer.