Downregulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer.
Downregulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer.
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乳腺癌预防的主要目标是减少早期乳腺癌--导管原位癌(DCIS)的发病率。然而，DCIS形成背后的生物学还没有被很好地理解。据推测，癌干细胞(CSCs)在癌前DCIS病变中已经被编程，这些肿瘤启动细胞可能决定DCIS的表型。配对DCIS肿瘤的microRNA(MiRNA)分析显示，miR-140丢失是DCIS病变的一个特征。以前，我们已经发现miR-140在管腔亚型浸润性导管癌中调节CSCs。在这里，我们发现miR-140在调节正常乳腺上皮和DCIS中的干细胞信号方面起着关键作用。对正常乳腺干细胞和来自DCIS肿瘤的癌症干细胞的miRNA图谱显示，与正常干细胞相比，癌症干细胞中miR-140的表达显著下调，连接了miR-140和调节失调的干细胞电路。此外，我们发现在DCIS干细胞样细胞中最显著激活的干细胞因子SOX9和ALDH1是miR-140的直接靶标。目前，靶向治疗(他莫昔芬)只能降低雌激素受体α(ERα)阳性疾病患者的DCIS风险。我们研究了ERα阴性/类基底细胞癌的模型，发现通过遗传方法或通过饮食化合物萝卜硫素恢复miR-140可以减少SOX9和ALDH1，并减少体内肿瘤的生长。这些结果支持miR-140/ALDH1/SOX9轴在基础CSC自我更新和体内肿瘤形成中起关键作用，提示miR-140通路可能是基底样DCIS患者预防策略的一个有前景的靶点。
The major goal of breast cancer prevention is to reduce the incidence of ductal carcinoma in situ (DCIS), an early stage of breast cancer. However, the biology behind DCIS formation is not well understood. It is suspected that cancer stem cells (CSCs) are already programmed in pre-malignant DCIS lesions and that these tumor-initiating cells may determine the phenotype of DCIS. MicroRNA (miRNA) profiling of paired DCIS tumors revealed that loss of miR-140 is a hallmark of DCIS lesions. Previously, we have found that miR-140 regulates CSCs in luminal subtype invasive ductal carcinoma. Here, we find that miR-140 has a critical role in regulating stem cell signaling in normal breast epithelium and in DCIS. miRNA profiling of normal mammary stem cells and cancer stem-like cells from DCIS tumors revealed that miR-140 is significantly downregulated in cancer stem-like cells compared with normal stem cells, linking miR-140 and dysregulated stem cell circuitry. Furthermore, we found that SOX9 and ALDH1, the most significantly activated stem-cell factors in DCIS stem-like cells, are direct targets of miR-140. Currently, targeted therapies (tamoxifen) are only able to reduce DCIS risk in patients with estrogen receptor α (ERα)-positive disease. We examined a model of ERα-negative/basal-like DCIS and found that restoration of miR-140 via a genetic approach or with the dietary compound sulforaphane decreased SOX9 and ALDH1, and reduced tumor growth in vivo. These results support that a miR-140/ALDH1/SOX9 axis is critical to basal CSC self-renewal and tumor formation in vivo, suggesting that the miR-140 pathway may be a promising target for preventative strategies in patients with basal-like DCIS.
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