Accession Number : ADA601803


Title :   Activation of Antitumorigenic Stat3beta in Breast Cancer by Splicing Redirection


Descriptive Note : Annual rept. 1 Jul 2012-30 Jun 2013


Corporate Author : MEMORIAL SLOAN-KETTERING CANCER CENTER NEW YORK


Personal Author(s) : Cartegni, Luca


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a601803.pdf


Report Date : Jul 2013


Pagination or Media Count : 27


Abstract : Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively active in a large number of tumors, where it works as a central player in the activation of multiple oncogenic pathways and contributes to the proliferative state, the migratory and invasive potential and to the maintenance of the mesenchymal phenotype. STAT3 therefore constitutes a potential prime target for directed cancer therapies. A naturally occurring alternative splicing variant, STAT3 , uses an alternative acceptor site within exon 23 and leads to the production of a truncated isoform, which lacks the C-terminal trans-activation domain (TAD). Depending on context, STAT3 can act as a dominant negative regulator of transcription and promote apoptosis. We have used modified antisense oligonucleotides to specifically induce a shift of expression from the abundant, active STAT3a to the truncated STAT3 isoform. Induction of the endogenous STAT3 leads to decreased cell viability in cell lines with persistent STAT3 tyrosine phosphorylation, compared to full STAT3 knock-down obtained by Forced Splicing-Dependent Nonsense-Mediated Decay (FSD-NMD). Furthermore, comparison of the molecular effects of splicing redirection to STAT3 knock-down reveals a unique STAT3b transcriptional signature, with the downregulation of specific target genes (including LEDGF, PCAF, Cyclin C, PEX1 and STAT1b) distinct from canonical STAT3 genes typically associated to total STAT3 knockdown. Here we propose to screen a next generation panel of antisense compounds, to reprogram STAT3 splicing in cancer cells in vitro and in vivo, in different genetic and orthotopic mouse models, to establish a working model system to test the approach.


Descriptors :   *BREAST CANCER , ELECTRON ACCEPTORS , GENES , GENETIC DISEASES , GENETIC MAPPING , GENETICS , NUCLEOTIDES


Subject Categories : Anatomy and Physiology
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE