Long non-coding RNA NORAD: a potential target for a promising human breast cancer therapy

• Autor(a) principal: Marcos, Carlota Tavares
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/40776
• topic: Breast cancer; Triple negative breast cancer; lncRNA NORAD; Chemotherapy

Breast cancer (BC) is a heterogeneous disease, being the most diagnosed cancer worldwide. Based on its molecular characteristics, BC can be classified into different subtypes. Triple negative breast cancer (TNBC) is the most aggressive subtype with little therapeutical options, presenting a more reserved prognostic. The long non-coding RNA activated by DNA damage (NORAD) has been associated with the progression of several cancers, but its role in BC remains controversial. Nevertheless, it is known that NORAD contributes to DNA protection and chromosomal stability by sequestering pumilio proteins, in normal conditions. The aims of the present work were to assess whether NORAD levels are associated with tumor aggressiveness and oncogenic transformation, to determine NORAD localization in TNBC cells, and to evaluate the effect of NORAD downregulation on the sensitivity of TNBC cells to doxorubicin, a chemotherapeutic agent. The results showed that NORAD expression levels tend to be higher in tissues from patients with more aggressive BC tumors, including luminal BC with high recurrence scores and TNBC with low response to treatment. Besides this, it was demonstrated by RNA fluorescence in situ hybridization, that NORAD localizes in the cytoplasm of TNBC cells. It was also found that NORAD participates in DNA damage response since NORAD knockdown contributed for the accumulation of DNA damage in doxorubicin-treated cells, sensitizing them for the treatment with this chemotherapeutic agent. Together, these results revealed the potential of NORAD as a prognostic and predictive biomarker, and as a therapeutical target in TNBC. Such findings could revolutionize TNBC treatment, with NORAD silencing serving as an adjunct to conventional chemotherapy, improving the prognosis of patients with TNBC.