Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
Carcinogenesis. 2021 Apr 30;42(4):528-536. doi: 10.1093/carcin/bgab005.
Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony-forming ability and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.
新出现的证据表明，microRNAs（miRNAs）在乳腺癌的发展中起着关键作用。我们最近报道，肿瘤组织中 miR-374b 的高表达与三阴性乳腺癌（TNBC）的无病生存更好相关。然而，miR-374b 在乳腺癌中的功能意义和分子机制在很大程度上尚不清楚。在本研究中，我们评估了 miR-374b 在 TNBC 和非 TNBC 中的生物学功能和潜在机制。我们发现，与相邻组织相比，乳腺癌组织中 miR-374b 显著下调。与乳腺上皮细胞相比，乳腺癌细胞系中的 miR-374b 水平也较低。体外和体内研究表明，miR-374b 调节乳腺癌细胞的恶性行为，如 2D 和 3D 中的细胞增殖、细胞侵袭能力、集落形成能力和小鼠中的肿瘤生长。通过使用生物信息学工具，我们预测 miR-374b 通过负调控细胞周期蛋白 D1（CCND1）和转化生长因子 alpha（TGFA）在乳腺癌细胞中发挥作用。我们进一步证实 CCND1 和 TGFA 在体外和体内促进乳腺癌细胞的恶性行为。我们的挽救实验表明，过表达 CCND1 或 TGFA 可逆转 miR-374b 过表达引起的表型。总之，我们的研究表明，miR-374b 通过负调控 CCND1 和 TGFA 基因来调节乳腺癌细胞的恶性行为。新发现的 miR-374b 介导的 CCND1 和 TGFA 基因沉默可能有助于更好地理解乳腺癌进展的分子机制。
