Cancer cells defy the normal rules of biology; they possess the ability to grow and thrive in an alarmingly uncontrolled manner. These properties can be traced back to the reliance of tumours on certain transcriptional pathways to maintain their rapid proliferation, a trait scientists call ‘transcription addiction’.
“Transcription addiction allows cancer cells to adapt, survive and spread,” explained Wee-Wei Tee, Co-Director of the Chromatin Dynamics and Disease Epigenetics Lab at A*STAR’s Institute of Molecular and Cell Biology (IMCB). “However, it also creates a vulnerability that can be targeted for potential treatments.”
For example, triple negative breast cancer (TNBC)—a highly aggressive cancer associated with poor clinical outcomes—typically relies on a uniform set of transcriptional programmes. Therefore, certain therapies may be more effective for treating TNBC by targeting these essential pathways.
Tee and IMCB colleagues, Radoslaw M. Sobota, Manikandan Lakshmanan and Vinay Tergaonkar, aimed to delve deeper into TNBC’s Achilles’ heel, to discover more transcription addiction pathways specifically associated with breast cancer progression and metastasis. In previous studies, the team had identified the Negative Elongation Factor (NELF) complex as a potential target: it acts as a control switch for a metastatic process called epithelial-mesenchymal transition (EMT).
Working with Ern Yu Tan from Tan Tock Seng Hospital and Wai Leong Tam from A*STAR’s Genome Institute of Singapore (GIS), the researchers performed a series of genomic and transcriptomic analyses in cancer cell lines and patient-derived tumour organoids. They also investigated the effects of depleting NELF in different cell lines and mouse models.
The researchers found that deactivating the NELF complex (using gene editing technologies) inhibited the spread and progression of breast cancer. Tee described how NELF-E, a component of the NELF complex interacted with a key EMT factor called SLUG: “Notably, SLUG emerged as one of the top interaction partners of NELF-E in the EMT state, suggesting a potential collaboration between the two proteins in driving metastasis.”
NELF-E-SLUG interactions were found to functionally impact KAT2B, a histone acetyltransferase that correlates with poorer prognosis in breast cancer patients. The exciting discovery by the research team points to NELF-E and KAT2B as targets which can unlock new breast cancer treatments.
“Preventing NELF-E from exerting its cancer-promoting effect can be achieved by modulating the activities of these binding partners that play crucial roles in cellular reprogramming,” Tee remarked.
Tee expressed that the team is leveraging these breakthrough findings to map more of NELF-E’s binding partners with crucial roles in cellular reprogramming, with the aim of one day offering hope to TNBC patients. “Despite TNBC representing only about 15 percent of all breast cancers, it stands out as a subtype with limited improvement and survival outcomes due to the lack of effective targeted therapies,” Tee concluded.