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:To identify novel molecular targets for triple negative breast cancer (TNBC), we have employed whole genome microarray expression profiling. We purified 30 surgically resected breast cancer tissue diagnosed triple negative by means of immunohistochemical staining and 13 normal mammary ductal cells with lasermicrobeam microdissection system (PALM MicroBeam, Carl Zeiss MicroImaging Co., Ltd), performed whole human genome microarray, and compared gene expression levels of TNBC, normal mammary ductal cells, and normal vital organs to develop molecular targets with a minimum risk. Gene expression levels of 30 TNBC, 13 normal mammary ductal cells, and 4 normal vital tissues were evaluated. to clarify the molecular mechanism involved in TNBC, we analyzed gene expression profiles of 30 TNBC as well as 13 normal epithelial ductal cells purified by laser microbeam microdissection, and identified 301 transcripts that were significantly up-regulated and 321 transcripts that were significantly down-regulated in TNBC. In addition, gene-expression profiles analysis of normal human vital organs including heart, lung, liver, and kidney allowed us to identify 90 cancer-specific genes involved in breast carcinogenesis such as NEK2, PBK, DTL, MELK and GPSM2. Among them, we focused on cell cycle regulators, asp (abnormal spindle) homolog, microcephaly associated (Drosophila) (ASPM) and centromere protein K (CENPK) as novel therapeutic targets for TNBC.
Project description:The aim of this study was evaluate the transcriptome changes in the comparison between triple negative tumors with increased SPARC expression and triple negative tumors with decreased SPARC expression according to Nagai et al., 2011 (Breast Cancer Res Treat (2011) 126:1–14) The results generated could be of particular interest to better define the prognostic impact of SPARC expression in triple negative breast tumors
Project description:This phase I trial is studying the side effects and best dose of giving 7-hydroxystaurosporine together with irinotecan hydrochloride in treating patients with metastatic or unresectable solid tumors, including triple-negative breast cancer (currently enrolling only patients with triple-negative breast cancer since 6/8/2007). Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving 7-hydroxystaurosporine together with irinotecan hydrochloride may help kill more cancer cells by making tumor cells more sensitive to the drug.