Negative growth regulatory role of ptpn11 shp2 in breast epithelial tumorigenesis

Abstract

Drosophila model system has played a pivotal role in the identification of genes involved at all stages of tumorigenesis An RNAi mediated screen of the Drosophila genome conducted in our laboratory identified putative negative regulators of growth in Epidermal Growth Factor Receptor EGFR and Yorkie Yki driven tumors In this study human orthologues of the RNAi mediated screen were subjected to detailed network analyses Enrichment of the protein protein interaction network among these putative growth regulators in humans identified major signaling pathways like the Hippo pathway and the mitogen activated protein kinase MAPK signaling pathway to be involved in driving both EGFR and the Yes associated protein 1 YAP1 a mammalian ortholog of Yki mediated tumorigenesis One of the identified negative growth regulators in the Yki screen but not a positive in the EGFR screen was corkscrew Csw a non receptor protein tyrosine phosphatase Tyrosine protein phosphatase type 11 PTPN11 encoding the Src Homology Phosphatase 2 SHP2 protein is one of the closest human orthologs of Csw and it is reported to be a bonafide oncogene in EGFR driven neoplasia However our clinical metadata analysis showed PTPN11 SHP2 functions as a putative tumor suppressor in breast adenocarcinoma BRCA Our analysis of dataset availed by the Molecular Taxonomy of Breast cancer International Consortium METABRIC 2012 showed PTPN11 SHP2 copy number loss in Luminal A subtype of breast cancer patient correlated to poor 4 years disease specific survival DSS and late stage cancer at diagnosis Furthermore our analysis of The Cancer Genome Atlas TCGA BRCA level 4 protein data showed low expression levels of active phospho SHP2 Y542 associated with larger tumor size and more lymph node positivity in Luminal A subtype of patients at diagnosis We experimentally investigated the possible role of PTPN11 SHP2 as a tumor suppressor in breast cancer Knockdown of PTPN11 SHP2 in MCF10A a non transformed breast epithelial cell line showed increased migration and c