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El Ghamrasni S.,Ontario Cancer Institute | Pamidi A.,Ontario Cancer Institute | Halaby M.J.,Ontario Cancer Institute | Bohgaki M.,Ontario Cancer Institute | And 10 more authors.
PLoS Genetics | Year: 2011

Chk2 is an effector kinase important for the activation of cell cycle checkpoints, p53, and apoptosis in response to DNA damage. Mus81 is required for the restart of stalled replication forks and for genomic integrity. Mus81Δex3-4/Δex3-4 mice have increased cancer susceptibility that is exacerbated by p53 inactivation. In this study, we demonstrate that Chk2 inactivation impairs the development of Mus81Δex3-4/Δex3-4 lymphoid cells in a cell-autonomous manner. Importantly, in contrast to its predicted tumor suppressor function, loss of Chk2 promotes mitotic catastrophe and cell death, and it results in suppressed oncogenic transformation and tumor development in Mus81Δex3-4/Δex3-4 background. Thus, our data indicate that an important role for Chk2 is maintaining lymphocyte development and that dual inactivation of Chk2 and Mus81 remarkably inhibits cancer. © 2011 El Ghamrasni et al.

Han Y.,Ontario Cancer Institute | Cui J.,Ontario Cancer Institute | Lu Y.,University of Toronto | Sue S.,The Campbell Family Institute for Breast Cancer Research | And 3 more authors.
Leukemia Research | Year: 2012

Acute myeloid leukemia (AML) is characterized by the growth and accumulation of cells blocked in their ability to differentiate, and blocks production of normal blood cells. The response to induction chemotherapy is heterogeneous, therefore biomarkers that predict for the outcome of such treatment are of potential value. FCHSD2 in a sensitized screen was identified as a potential chemo-protector (TW Mak, unpublished). In the present study, we found that FCHSD2 knockdown by shRNA could enhance chemosensitivity of U937 cells. This coincided with the increased expression of p21 and PUMA as well as the decreased expression of Bcl-2, c-myc and hTERT. In contrast, over-expression of FCHSD2 significantly increased cellular chemoresistance. To see if there was potential clinical relevance of FCHSD2 expression in leukemia we used qRT-PCR to assess FCHSD2 expression levels in peripheral blood or bone marrow blasts of 71 AML patients. There was an inverse correlation between the level of FCHSD2 with overall survival time (r=-0.7647, p<0.0001) and relapse free time (r=-0.8165, p<0.0001). By dividing patients into high and low expression groups using a FCHSD2 expression threshold value of 0.001, the median survival of the high expression group (72 days) was shorter than in the low expression group (2472 days). The average FCHSD2 expression level in 41 patients with complete remission was significantly lower than that in 30 non-responder patients (p<0.0001). Moreover, in 32 de novo AML patients receiving initial remission-induction chemotherapy, we confirmed that the patients with lower FCHSD2 expression prior to the treatment had an increased chance of attaining remission compared to patients with high level FCHSD2. In conclusion, our study, for the first time, demonstrates FCHSD2 as a predictor of outcome for AML patient. The determination of FCHSD2 expression at the time of diagnosis could help to identify the responses of AML patients to chemotherapy. © 2012 Elsevier Ltd.

Mason J.,The Campbell Family Institute for Breast Cancer Research | Lin D.-C.,The Campbell Family Institute for Breast Cancer Research | Wei X.,The Campbell Family Institute for Breast Cancer Research | Che Y.,The Campbell Family Institute for Breast Cancer Research | And 9 more authors.
Cancer Cell | Year: 2014

PLK4 was identified as a promising therapeutic target through a systematic approach that combined RNAi screening with gene expression analysis in human breast cancers and cell lines. A drug discovery program culminated in CFI-400945, a potent and selective PLK4 inhibitor. Cancer cells treated with CFI-400945 exhibit effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication, mitotic defects, and cell death. Oral administration of CFI-400945 to mice bearing human cancer xenografts results in the significant inhibition of tumor growth at doses that are well tolerated. Increased antitumor activity invivo was observed in PTEN-deficient compared to PTEN wild-type cancer xenografts. Our findings provide a rationale for the clinical evaluation of CFI-400945 in patients with solid tumors, in particular those deficient in PTEN. © 2014 Elsevier Inc.

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