Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
Oncogene. 2014 May 15;33(20):2589-600. doi: 10.1038/onc.2013.226. Epub 2013 Jun 10.
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.
乳腺癌预防的主要目标是降低导管原位癌（DCIS）的发病率，这是乳腺癌的早期阶段。然而，DCIS 形成的生物学机制尚不清楚。人们怀疑癌症干细胞（CSC）已经在癌前的 DCIS 病变中编程，这些肿瘤起始细胞可能决定 DCIS 的表型。对配对的 DCIS 肿瘤进行 microRNA（miRNA）谱分析表明，miR-140 的缺失是 DCIS 病变的一个标志。以前，我们发现 miR-140 调节腔型浸润性导管癌中的 CSCs。在这里，我们发现 miR-140 在正常乳腺上皮和 DCIS 中调节干细胞信号具有关键作用。对正常乳腺干/DCIS 肿瘤中的癌症干细胞样细胞进行 miRNA 谱分析表明，与正常干细胞相比，miR-140 在癌症干细胞样细胞中显著下调，将 miR-140 与失调的干细胞信号通路联系起来。此外，我们发现 SOX9 和 ALDH1，即 DCIS 干细胞样细胞中最显著激活的干细胞因子，是 miR-140 的直接靶标。目前，靶向治疗（他莫昔芬）仅能降低雌激素受体 α（ERα）阳性疾病患者的 DCIS 风险。我们检查了一种 ERα-阴性/基底样 DCIS 模型，发现通过遗传方法或饮食化合物萝卜硫素恢复 miR-140 可降低 SOX9 和 ALDH1 的表达，并减少体内肿瘤生长。这些结果支持 miR-140/ALDH1/SOX9 轴对基底 CSC 自我更新和体内肿瘤形成至关重要，表明 miR-140 通路可能是基底样 DCIS 患者预防策略的一个有前途的靶点。
