Eldad Zacksenhaus, PhD

Breast Cancer (BC)
In North America, the life-long incidence of BC is ~10%. The disease is heterogeneous and can be subdivided into three subtypes: ER+, HER2/NEU+ and triple negative tumors (TNT), the latter of which does not express hormone receptors or HER2/NEU. Specific treatments exist for ER+ and HER2+ but not TNTs; metastatic disease is virtually untreatable. To identify novel therapeutic targets we are using a mouse model for HER2/NEU+ BC (MMTV-Neu; Muller) and two models of TNTs, which we have developed based on inactivation of the tumour suppressors Rb or Pten in the mammary epithelium. In particular, we are interested in identifying and targeting tumour-initiating cells and early dissemination cancer cells, which are thought to drive tumour growth and spread.

a. We have identified tumour-initiating cells (TICs) in HER2/NEU mammary tumours and we are currently developing a specific TIC signature as well as screening for therapeutic targets using shRNA and small chemical libraries.

The Retinoblastoma Protein (Rb)
Rb plays a crucial role in regulating cell proliferation and survival and possibly terminal differentiation, and is mutated or functionally inactivated in virtually all human malignancies. Using loss- and gain-of-function approaches we are investigating the effects of Rb on embryonic development, homeostasis and cancer, as well as the mechanisms by which it exerts these diverse biological functions.

a. Previously, we showed that mouse embryos lacking Rb develop severe muscle defects including ectopic proliferation, cell death and abortive differentiation and degeneration. We have recently shown that the myogenic differentiation defect and degeneration could be rescued in vitro by survival factors, autophagy inhibitors or hypoxia. We have also determined the effect of combined mutations in all Rb protein family on myogenesis. Alternative roles for Rb in development and differentiation as well as its role in hypoxia and cell metabolism are currently being investigated.

b. Rb is primarily regulated by phosphorylation via cyclin-dependent kinases. pRb is hypo-phosphorylated and active in G0/G1 and then sequentially phosphorylated and inactivated by D and E type cyclins. We previously showed that expression of constitutively active phospho-mutant pRb transgenes inhibits cell proliferation but paradoxically induces tumours. To investigate the effect of blocking endogenous phosphorylation of Rb, we use a knockin approach to mutate key phosphorylation sites in Rb and test their impact in vitro and in vivo.
Sci Rep. 2019 Dec 13;9(1):19107
Wang DY, Jiang Z, Ben-David Y, Woodgett JR, Zacksenhaus E
Leukemia. 2019 Nov 14;:
Ren Z, Shrestha M, Sakamoto T, Melkman T, Meng L, Cairns RA, Zacksenhaus E, Mak TW, Stambolic V, Minden MD, Wang JA
BMC Cancer. 2019 Aug 02;19(1):764
Wang N, Fan Y, Yuan CM, Song J, Yao Y, Liu W, Gajendran B, Zacksenhaus E, Li Y, Liu J, Hao XJ, Ben-David Y
Cell Death Dis. 2019 Feb 11;10(2):117
Liu T, Xia L, Yao Y, Yan C, Fan Y, Gajendran B, Yang J, Li YJ, Chen J, Filmus J, Spaner DE, Zacksenhaus E, Hao X, Ben-David Y
Bioorg Med Chem. 2018 Nov 16;:
Xiao X, Xu M, Yang C, Yao Y, Liang LN, Ed Chung P, Long Q, Zacksenhaus E, He Z, Liu S, Ben-David Y
FEBS J. 2018 Nov 02;:
Song J, Yuan C, Yang J, Liu T, Yao Y, Xiao X, Gajendran B, Xu D, Li YJ, Wang C, Liu W, Wen M, Spaner D, Filmus J, Zacksenhaus E, Zhang Y, Hao X, Ben-David Y
Cell Rep. 2018 Oct 16;25(3):702-714.e6
An Y, Adams JR, Hollern DP, Zhao A, Chang SG, Gams MS, Chung PED, He X, Jangra R, Shah JS, Yang J, Beck LA, Raghuram N, Kozma KJ, Loch AJ, Wang W, Fan C, Done SJ, Zacksenhaus E, Guidos CJ, Perou CM, Egan SE
Mol Cell Oncol. 2018;5(4):e1481814
Zacksenhaus E, Liu JC, Granieri L, Vorobieva I, Wang DY, Ghanbari-Azarnier R, Li H, Ali A, Chung PED, Ju Y, Jiang Z, Shrestha M
Oncotarget. 2018 Jul 24;9(57):30940-30941
Knudsen ES, Zacksenhaus E


Professor, Departments of Medicine, Laboratory Medicine & Pathobiology and Medical Biophysics, University of Toronto