Roles of microRNA-140 in stem cell-associated early stage breast cancer.
Roles of microRNA-140 in stem cell-associated early stage breast cancer.
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DOI：
10.4252/wjsc.v6.i5.591
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发表时间：
2014-11
影响因子：
4.1
通讯作者：
Benjamin Wolfson;Gabriel L Eades;Qun Zhou
中科院分区：
文献类型：
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作者：
Benjamin Wolfson;Gabriel L Eades;Qun Zhou
越来越多的证据支持乳腺癌从导管原位癌（DCIS）进展为浸润性导管癌（IDC）的逐步模型。由于DCIS异质性高，我们目前无法预测哪些患者的疾病复发或进展风险最高。进展的机制在很大程度上仍然是未知的，但是DCIS病变中的癌症干细胞群可能作为恶性前体细胞密切参与进展。虽然在DCIS中发现的遗传和表观遗传改变通常与IDC相同，但mRNA和miRNA表达谱发生显著改变。靶向治疗癌症干细胞通路和差异表达的miRNA可能具有显著的临床益处。随着肿瘤分级的增加，miRNA-140逐渐下调。miR-140在Wnt、SOX 2和SOX 9干细胞调节通路中发挥重要的肿瘤抑制作用。miR-140的下调消除了对这些途径的抑制，导致更高的癌症干细胞群体和乳腺癌进展。miR-140下调是通过miR-140启动子区的雌激素反应元件和CpG岛的差异甲基化介导的。这些机制是表观遗传疗法通过miR-140激活肿瘤抑制信号传导的新靶点。此外，我们简要探讨了外泌体在介导细胞间miR-140信号传导中的新作用。本综述的目的是研究乳腺癌进展中涉及的癌症干细胞信号通路，以及miR-140失调在调节DCIS向IDC转变中的作用。
An increasing body of evidence supports a stepwise model for progression of breast cancer from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Due to the high level of DCIS heterogeneity, we cannot currently predict which patients are at highest risk for disease recurrence or progression. The mechanisms of progression are still largely unknown, however cancer stem cell populations in DCIS lesions may serve as malignant precursor cells intimately involved in progression. While genetic and epigenetic alterations found in DCIS are often shared by IDC, mRNA and miRNA expression profiles are significantly altered. Therapeutic targeting of cancer stem cell pathways and differentially expressed miRNA could have significant clinical benefit. As tumor grade increases, miRNA-140 is progressively downregulated. miR-140 plays an important tumor suppressive role in the Wnt, SOX2 and SOX9 stem cell regulator pathways. Downregulation of miR-140 removes inhibition of these pathways, leading to higher cancer stem cell populations and breast cancer progression. miR-140 downregulation is mediated through both an estrogen response element in the miR-140 promoter region and differential methylation of CpG islands. These mechanisms are novel targets for epigenetic therapy to activate tumor suppressor signaling via miR-140. Additionally, we briefly explored the emerging role of exosomes in mediating intercellular miR-140 signaling. The purpose of this review is to examine the cancer stem cell signaling pathways involved in breast cancer progression, and the role of dysregulation of miR-140 in regulating DCIS to IDC transition.