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转化生长因子β/细胞周期蛋白D1/ Smad介导的骨形态发生蛋白4抑制作用促进乳腺癌干细胞自我更新活性。

TGFβ/cyclin D1/Smad-mediated inhibition of BMP4 promotes breast cancer stem cell self-renewal activity.

作者信息

Yan Gang, Dai Meiou, Zhang Chenjing, Poulet Sophie, Moamer Alaa, Wang Ni, Boudreault Julien, Ali Suhad, Lebrun Jean-Jacques

机构信息

McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada.

Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.

出版信息

Oncogenesis. 2021 Mar 1;10(3):21. doi: 10.1038/s41389-021-00310-5.

DOI:10.1038/s41389-021-00310-5
PMID:33649296
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7921419/
Abstract

Basal-like triple-negative breast cancers (TNBCs) display poor prognosis, have a high risk of tumor recurrence, and exhibit high resistance to drug treatments. The TNBC aggressive features are largely due to the high proportion of cancer stem cells present within these tumors. In this study, we investigated the interplay and networking pathways occurring between TGFβ family ligands in regulating stemness in TNBCs. We found that TGFβ stimulation of TNBCs resulted in enhanced tumorsphere formation efficiency and an increased proportion of the highly tumorigenic CD44/CD24 cancer stem cell population. Analysis of the TGFβ transcriptome in TNBC cells revealed bone morphogenetic protein4 (BMP4) as a main TGFβ-repressed target in these tumor cells. We further found that BMP4 opposed TGFβ effects on stemness and potently decreased cancer stem cell numbers, thereby acting as a differentiation factor in TNBC. At the molecular level, we found that TGFβ inhibition of BMP4 gene expression is mediated through the Smad pathway and cyclin D1. In addition, we also found BMP4 to act as a pro-differentiation factor in normal mammary epithelial cells and promote mammary acinar formation in 3D cell culture assays. Finally, and consistent with our in vitro results, in silico patient data analysis defined BMP4 as a potential valuable prognosis marker for TNBC patients.

摘要

基底样三阴性乳腺癌（TNBC）预后较差，肿瘤复发风险高，且对药物治疗具有高度抗性。TNBC的侵袭性特征很大程度上归因于这些肿瘤中存在的高比例癌症干细胞。在本研究中，我们调查了TGFβ家族配体之间在调节TNBC干性方面发生的相互作用和网络通路。我们发现，TGFβ刺激TNBC会导致肿瘤球形成效率提高，以及高致瘤性CD44/CD24癌症干细胞群体比例增加。对TNBC细胞中TGFβ转录组的分析显示，骨形态发生蛋白4（BMP4）是这些肿瘤细胞中主要受TGFβ抑制的靶点。我们进一步发现，BMP4对抗TGFβ对干性的影响，并有效减少癌症干细胞数量，从而在TNBC中作为一种分化因子发挥作用。在分子水平上，我们发现TGFβ对BMP4基因表达的抑制是通过Smad通路和细胞周期蛋白D1介导的。此外，我们还发现BMP4在正常乳腺上皮细胞中作为一种促分化因子发挥作用，并在3D细胞培养试验中促进乳腺腺泡形成。最后，与我们的体外结果一致，计算机模拟患者数据分析将BMP4定义为TNBC患者潜在的有价值的预后标志物。

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