Project description:NEK2 is a mitotic kinase that is upregulated and mislocalized in the nucleus of human cancer cells. NEK2 modulates expression and activity of both transcription and splicing factors in cancer cells, nevertheless whether this kinase affects transcriptome regulation genome widely and whether this activity concurs to its oncogenic activity is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 cells transiently silenced for NEK2 we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this kinase.
Project description:ADAR1 catalyzes Adenosine-to-Inosine (A-to-I) editing of double-stranded RNA and regulates global expression output through its interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is important for growth and invasion in triple negative breast cancer cells, as ADAR1 loss yields reduced growth, migration & invasion, and mammosphere formation. Global RNA-seq analyses demonstrate that ADAR1 regulates both coding and non-coding targets via expression level and/or A-to-I editing. We demonstrated that a recoding edit in FLNB (chr3:58156064) inhibits the tumor suppressive activities of the protein to promote growth & invasion. We show that several tumor suppressor microRNAs are also downregulated by ADAR1 to promote cell cycle progression and invasion. This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple negative breast cancer, providing support to strategies for targeting ADAR1 in this aggressive cancer type with few treatment options.
Project description:Breast cancers enriched for the triple negative breast cancer phenotype with extensive clinico-pathological features were profiled to establish their comprehensive transcriptional profiles
Project description:We propose to definitively characterise the somatic genetics of triple negative breast cancer through generation of comprehensive catalogues of somatic mutations in breast cancer cases by high coverage genome sequencing coupled with integrated transcriptomic and methylation analyses.
Project description:Breast cancer is one of the most common cancers in women. Of the different subtypes of breast cancer, the triple negative breast cancer subtype of breast cancer is the most aggressive. A proteomic screen of nucleolar content across breast cancer subtypes found that triple negative breast cancer cell lines have a distinct nucleolar proteome signature in comparison to non-TNBC breast cancer cell lines.