RNA export factors and non-coding RNAs in breast cancer

Breast cancer (BC) is one of the most common diagnosed human cancers in women and accounts for 30% of all cancer diagnoses in women. Surgery of the primary tumor is the treatment of choice in localized stages with the aim of curative chances. Although several patients are cured by this treatment modality, some of them develop metastatic disease or are diagnosed with primary metastatic BC. Once metastasized, BC represents an incurable disease in all patients. BC is a heterogeneous disease in terms of biology, treatment success and patients prognosis. The triple negative BC (TNBC) subtype, which is defined by the lack of three (estrogen, progesterone and HER2) immunohistochemical detectable receptors, is the most aggressive subtype. Unfortunately, this subtype is frequently found in young women and more or less cytotoxic chemotherapy is the mainstay of therapeutic intervention. Therefore, the identification of the molecular mechanisms that drive and maintain metastatic TNBC might enable a better understanding of the pathogenesis, a better risk-stratification of patients with localized disease and the identification of novel drug targets. The central hypothesis of this Hertha Firnberg research proposal is to determine the role of nuclear RNA export factors and long non-coding RNAs in TNBC and discover novel therapeutic vulnerabilities. To achieve this, we will use a three-aimed strategy including genome-wide aberrations in transcription, metabolism and mitochondrial function and therapeutic approaches to identify new factors and new targets for lncRNA-based drug therapy.

This research delves into the role of a protein called ALYREF in breast cancer development. ALYREF is known for its involvement in controlling the process of gene expression and the transport of genetic material within the cell nucleus. However, its specific role in breast cancer has not been thoroughly understood until now. The study reveals that high levels of ALYREF are associated with poorer survival outcomes in breast cancer patients. Through various experiments conducted in breast cancer cells and animal models, we found that ALYREF significantly influences cell growth, programmed cell death (apoptosis), and the energy metabolism of mitochondria, which are crucial organelles responsible for producing energy in cells. We identified a long non-coding RNA (lncRNA) called NEAT1 as a key player in mediating the effects of ALYREF in breast cancer. Specifically, we discovered that ALYREF binds to the promoter region of NEAT1 and enhances its overall activity, leading to increased production of a shorter isoform of NEAT1. Importantly, ALYREF selectively regulates the expression of this short NEAT1 isoform by stabilizing a protein called CPSF6, which is involved in generating this isoform. This regulation mechanism fine-tunes the levels of the short NEAT1 isoform, which is known to play a significant role in breast cancer progression. The study also sheds light on the clinical relevance of ALYREF in breast cancer. Analysis of patient data revealed that ALYREF gene amplification is common in various cancers, including breast cancer, and high ALYREF expression levels are associated with poor clinical outcomes. These findings suggest that ALYREF could serve as a potential prognostic biomarker for breast cancer patients, helping to identify individuals at higher risk. Furthermore, experiments showed that reducing ALYREF expression led to decreased tumor formation in animal models, suggesting that targeting ALYREF could be a potential therapeutic strategy for treating breast cancer, particularly the aggressive triple-negative subtype. In conclusion, this research uncovers a novel role for ALYREF in triple-negative breast cancer (TNBC) development and progression. By elucidating the molecular mechanisms through which ALYREF influences breast cancer biology, the study opens up new avenues for therapeutic interventions and highlights the potential of ALYREF as a prognostic marker for TNBC patients. Further research and clinical trials are needed to fully explore the therapeutic implications of targeting ALYREF in breast cancer treatment.