Endocrine Abstracts

The dysregulation of the splicing process has emerged as a novel hallmark of metabolic and tumor pathologies. Specifically, in breast cancer (BCa), which represents the most diagnosed cancer type among women worldwide, several oncogenic splicing variants have been reported to have a relevant pathophysiological role. This is the case of the splicing variants of HER2 gene, or the In1-ghrelin and SST5TMD4 isoforms, which exhibit oncogenic roles, increasing the malignancy, poor prognosis and resistance to treatment of BCa. However, the implication and putative dysregulation of the elements belonging to the macromolecular machinery that regulate the splicing process [spliceosome components (SCs) and the associated splicing factors (SFs)] have not been systematically explored in BCa. Similarly, the impact of the metabolic status (i.e. obesity) of the patients on the regulation of the splicing machinery in the context of BCa has not been explored. A recent study from our group has characterized the expression pattern of key SCs (n = 17) and associated SFs (n = 28) in the tissue of 69 patients with BCa and 50 non-tumoral controls, demonstrating a profound dysregulation of the splicing machinery in BCa samples (i.e. upregulation of ESRP1 or SRSF10 and downregulation of CELF4, NOVA1 or PTBP1). These alterations have been found in other external cohorts (TCGA, Curtis) and correlate with the expression of oncogenic splicing variants, poor prognosis and reduced survival of the patients. Interestingly, the obesity and post-menopausal status clearly influenced the expression levels of certain splicing machinery components (i.e. SRSF3 or SRSF9) under normal and/or tumoral (BCa) conditions. In addition, the experimental modulation of these altered factors impacted the aggressiveness and tumorigenic potential of different BCa cell lines. In conclusion, there are growing evidence indicating that splicing machinery is deeply dysregulated in BCa samples, finely influenced by obesity and menopausal status and implicated in the tumorigenic potential of BCa cells.