Date of Award
Doctor of Philosophy (PhD)
Genetics, Cell Biology & Anatomy
Dr. Vimla Band
Breast cancer is the second leading cause of cancer related deaths in women in the United States. The human Epidermal Growth Factor 2 (ErbB2) gene amplification and/or receptor overexpression subtype of breast cancer accounts for 25% of all breast cancers. A crucial regulator of the ErbB2 signaling pathway is the heat shock protein 90 (Hsp90) and its interacting protein complex. One such complex is the R2TP/Prefoldin-like complex that is composed of four proteins, RUVBL1, RUVBL2, PIH1D1, and RPAP3 and seven prefoldin-like proteins. This complex has been shown to be involved in telomere elongation, ribosome biogenesis, protein stability; etc. We and others have recently shown that Ecdysoneless (ECD) protein functions as a mediator for interaction of HSP90 and the R2TP complex and determines which intracellular molecules the chaperone complex will regulate. Ecdysoneless, was first discovered as a Drosophila fly mutation and we later identified the mammalian ortholog of ECD in human epithelial cells as a binding partner of human papilloma virus 16 E6 oncoprotein. Using knockout gene strategy we demonstrated that ECD deletion is embryonic lethal and its knockdown or knockout (using fl/fl mouse embryonic fibroblasts and adenovirus cre mediated deletion) in vitro led to block in cell cycle progression. Subsequently, we demonstrated ECD is overexpressed in breast cancers, specifically in ErbB2+ breast cancers and its overexpression correlates with poor prognosis and poor survival in these patients.
As part of my thesis work, I investigated how ECD regulates cell cycle progression and the role of ECD in ErbB2-driven oncogenesis. We showed that ECD is phosphorylated on several serine residues by CK2 that are important for ECD’s cell cycle function. In second goal, we have shown a novel interaction between ErbB2 and ECD, and knockdown of ECD deregulates the stability of the ERBB2 and HSP90 complex and leads to downregulation of ErbB2 and consequently decreased expression of downstream effectors. We speculate ECD functions as a co-oncogene in ErbB2-driven breast cancer and future studies using transgenic models will explore this possibility.
Ammons, Shalis A., "Role of ECDYSONELESS in ERBB2/HER2 Mediated Breast Oncogenesis" (2016). Theses & Dissertations. 107.
Available for download on Sunday, April 29, 2018