TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis

Abstract

Background 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. Methods 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. 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. 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. 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.

Treacle is Upregulated in Cancer and Correlates With Poor Prognosis

“…Furthermore, the authors investigated the association between Treacle status and patient outcome and demonstrated that high levels of Treacle expression correlated with poor survival both in TNBC and across all breast cancers. In the case of TNBC patients, correlation between Treacle expression, tumor grade, and TNM stage was observed, pointing to a role of Treacle in advanced stages of cancer in TNBC patients ( Hu et al, 2022 ).…”

“…Another recent study by Hu et al showed that Treacle mRNA is upregulated in 32% of triple negative breast cancers (TNBC) ( Hu et al, 2022 ). The upregulation of Treacle was validated at the protein level in breast cancer cell lines and by immunohistochemistry in a cohort of breast cancer patients ( Hu et al, 2022 ). Furthermore, the authors investigated the association between Treacle status and patient outcome and demonstrated that high levels of Treacle expression correlated with poor survival both in TNBC and across all breast cancers.…”

“…Another recent study by Hu et al showed that Treacle mRNA is upregulated in 32% of triple negative breast cancers (TNBC) ( Hu et al, 2022 ). The upregulation of Treacle was validated at the protein level in breast cancer cell lines and by immunohistochemistry in a cohort of breast cancer patients ( Hu et al, 2022 ).…”

“…The importance of growth and proliferation in relation to cancer development was also assessed by Hu et al, 2022 , studying tumor incidence upon injection of spheroids with or without Treacle knockout in the mammary fat pad of female nude mice. Mice injected with Treacle knockout cells showed significantly less tumor incidence, as well as lower frequency of tumor-initiating cells in comparison to the controls ( Hu et al, 2022 ).…”

Treacle Sticks the Nucleolar Responses to DNA Damage Together

“…Treacle upregulation is however emerging as a tumor promoting factor. Elevated Treacle levels correlated with poor prognosis, and shorter survival in different cancer types ( Gu et al, 2022 ; Hu et al, 2022 ; Wu et al, 2022 ). This could be attributed to Treacle’s function in facilitating rRNA transcription.…”