MOLECULAR CHARACTERIZATION OF GREB1 AND TRAF3 IN THE ONCOGENIC SIGNALLING PATHWAYS OF HUMAN CANCER

Abstract

Deregulation of cell signalling pathwaysthat control growth and cell fate is one of the most important hallmarks of human cancer.NF-κBpathwaydysregulationis critical for the pathogenesis of human cancers. Mutation of TRAF3; an upstream adapter molecule constitutively activatesthis pathwayinMultiple Myeloma. I found TRAF3 mutation underliesthe de-novo survival andthe acquisition of proteasome inhibitor resistance (PIR). I identified key players in the mechanism of PIR.ER+ breast cancer also uses ERαto sustain proliferative signalling. Growth regulation by Estrogen in Breast Cancer 1 (GREB1) is one of the top E2 responsive ERα target genes. Loss of GREB1 results in cell proliferation defects by attenuating ER signalling. However, the molecular mechanism by which GREB1 affects ER-associated tumor growth is barely known. I identified GREB1 is a novel glycosyltransferase enzyme which glycosylates and stabilizes ERα and subsequently promotestumor growth. Loss of GREB1 confers tamoxifen resistance.