Background: Despite today's advances in the treatment of cancer, breast cancer-related mortality remains high, in part due to the lack of effective targeted therapies against breast tumor types that do not respond to standard treatments. Therefore, identifying additional breast cancer molecular targets is urgently needed. Super-enhancers are large regions of open chromatin involved in the overactivation of oncogenes. Thus, inhibition of super-enhancers has become a focus in clinical trials for its therapeutic potential. Here, we aimed to identify novel super-enhancer dysregulated genes highly associated with breast cancer patients' poor prognosis and negative response to treatment.
Methods: Using existing datasets containing super-enhancer-associated genes identified in breast tumors and public databases comprising genomic and clinical information for breast cancer patients, we investigated whether highly expressed super-enhancer-associated genes correlate to breast cancer patients' poor prognosis and to patients' poor response to therapy. Our computational findings were experimentally confirmed in breast cancer cells by pharmacological SE disruption and gene silencing techniques.
Results: We bioinformatically identified two novel super-enhancer-associated genes - NSMCE2 and MAL2 - highly upregulated in breast tumors, for which high RNA levels significantly and specifically correlate with breast cancer patients' poor prognosis. Through in-vitro pharmacological super-enhancer disruption assays, we confirmed that super-enhancers upregulate NSMCE2 and MAL2 transcriptionally, and, through bioinformatics, we found that high levels of NSMCE2 strongly associate with patients' poor response to chemotherapy, especially for patients diagnosed with aggressive triple negative and HER2 positive tumor types. Finally, we showed that decreasing NSMCE2 gene expression increases breast cancer cells' sensitivity to chemotherapy treatment.
Conclusions: Our results indicate that moderating the transcript levels of NSMCE2 could improve patients' response to standard chemotherapy consequently improving disease outcome. Our approach offers a new avenue to identify a signature of tumor specific genes that are not frequently mutated but dysregulated by super-enhancers. As a result, this strategy can lead to the discovery of potential and novel pharmacological targets for improving targeted therapy and the treatment of breast cancer.
Keywords: Breast cancer; MAL2; NSMCE2; Super-enhancers; Therapy resistance.
© 2022. The Author(s).