Abstract
BackgroundTriple-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.MethodsOverall 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.ResultsTCOF1 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.ConclusionsTCOF1 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.
Highlights
Breast cancer remains the second most common cause of death of women worldwide despite recent advances in diagnosis and treatment [1]
TCOF1 depletion attenuates stemness of Triple-negative breast cancer (TNBC) Since our data of clonogenic assay suggest that TCOF1 regulates progeny producing capability, we investigated if TCOF1 regulates cancer stem cells (CSCs) properties and tumour-initiating ability
We examined the effects of TCOF1 on downstream pathways of KIT, and our results indicated that phosphorylation of KIT, AKT, STAT3 and ERK was inhibited upon TCOF1 knockout (Fig. 4c)
Summary
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. We recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Our data revealed TCOF1 as a putative TNBC-specific super-enhancer-regulated gene. The effect of TCOF1 knockout on TNBC growth and stemness was evaluated by in vitro and in vivo assays. RESULTS: 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. TCOF1 expression in TNBC is regulated by the predicted super-enhancer. CONCLUSIONS: 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
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