Investigate a potential link between sensitivity of basal subtype of  Breast Cancer BCa to RNAP1 inhibitors and the levels of activated rRNA synthesis.


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Sameerh Alsahafi1,Dr. Konstantin Panov1,Professor.ross Hannan2
1Queens University Belfast,2John Curtin School of Medical Research, ANU

Abstract

Background

Cancer has been identified as a group of diseases characterized by abnormal cell growth and uncontrollably by up-regulation of the normal cell. The most frequently diagnosed cancer in women is breast cancer. BCa is characterised high heterogeneity and based on gene expression profiles, its classified into 5 subgroups: luminal A, Luminal B, basal-like, Her2/Neu amplified, and normal-like. Basal-like tumours are usually aggressive, with strong tendency to metastasis and hence poor prognosis. In eukaryotic cells, the nucleolus is the region of the nucleus that constructs ribosomal subunits. The nucleolar size correlates with the level of rRNA synthesis, which is transcribed by RNA polymerase 1 (RNAP1) during the initial stage of ribosome biogenesis. A characteristic feature of uncontrolled cancer cell proliferation is associated with the increased transcription of rRNAs. In recent years the rRNA transcription has emerged as a novel target for anticancer therapy, and specific RNAP1 transcription inhibitors are currently undergoing clinical trials for patients with advanced haematological malignancies the consequence of the rupture of the nucleus and activation of p53, depending on apoptosis. The currently available inhibitors are characterised by a different mechanism and different levels of genotoxicity. The currently available inhibitors are characterised by a different mechanism and different levels of genotoxicity.four drugs:CX-5461, BMH-21, PMR-116 and 9HE are small molecules and selective inhibitors of RNAP1 transcription which have moderate effect on transcription by other nucleolar polymerases and protein translation and which are at different stages of clinical development. CX-5461 inhibits transcription by displacing essential promoter recognition factor SL1 thus preventing an initiation of transcription. BMH-21 inhibits elongation and induces rapid degradation of RNAP1. 9-Hydroxyellipticine (9HE) Selecting ellipticine derivatives that were capable of intercalating into DNA with a high affinity. PMR-116 demonstrated a great potential as RNAP1 inhibitor, and characterized by low cytotoxity and very high anti-cancer effect. However, the exact molecular mechanisms of RNAP1 inhibition is unknown. Therefore, here we aim to investigate the mechanism PMR116 action in breast cancer cells.

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