Tung Biomedical Sciences Centre, Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong.
City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
Br J Cancer. 2022 Jan;126(1):57-71. doi: 10.1038/s41416-021-01596-3. Epub 2021 Oct 30.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Our data also revealed TCOF1 as a putative TNBC-specific super-enhancer-regulated gene. TCOF1 plays a critical role in craniofacial development but its function in cancer remains unclear.
Overall survival and multivariant Cox regression analyses were conducted using the METABRIC data set. The effect of TCOF1 knockout on TNBC growth and stemness was evaluated by in vitro and in vivo assays. RNA-seq and rescue experiments were performed to explore the underlying mechanisms.
TCOF1 is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. TCOF1 depletion significantly inhibits the growth and stemness of basal-like TNBC, but not of mesenchymal-like cells, highlighting the distinct molecular dependency in different TNBC subgroups. RNA-seq uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that KIT is a downstream effector of TCOF1 in mediating TNBC stemness. TCOF1 expression in TNBC is regulated by the predicted super-enhancer.
TCOF1 depletion potently attenuates the growth and stemness of basal-like TNBC. Expression of TCOF1 may serve as a TNBC prognostic marker and a therapeutic target.
三阴性乳腺癌（TNBC）是一种预后较差的侵袭性乳腺癌亚型。通过进行多组学分析，我们最近发现乳腺癌亚型之间存在超级增强子异质性。我们的数据还揭示了 TCOF1 是一种假定的 TNBC 特异性超级增强子调控基因。TCOF1 在颅面发育中发挥着关键作用，但它在癌症中的功能尚不清楚。
使用 METABRIC 数据集进行总生存和多变量 Cox 回归分析。通过体外和体内实验评估 TCOF1 敲除对 TNBC 生长和干性的影响。进行 RNA-seq 和挽救实验以探索潜在的机制。
TCOF1 在 TNBC 中频繁上调，其表达水平升高与总生存期缩短相关。TCOF1 耗竭显著抑制基底样 TNBC 的生长和干性，但对间质样细胞没有影响，这突出了不同 TNBC 亚组中分子依赖性的明显差异。RNA-seq 揭示了 TCOF1 调控的几个干细胞分子。我们进一步证明 KIT 是 TCOF1 介导 TNBC 干性的下游效应物。TNBC 中 TCOF1 的表达受预测超级增强子的调控。
TCOF1 耗竭可有效减弱基底样 TNBC 的生长和干性。TCOF1 的表达可以作为 TNBC 的预后标志物和治疗靶点。
