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Kasler H.G.,Gladstone | Lim H.W.,Gladstone | Mottet D.,Gladstone | Mottet D.,Metastasis Research Laboratory | And 3 more authors.
EMBO Journal | Year: 2012

Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-ΔP) in thymocytes. We find that HDAC7-ΔP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. © 2012 European Molecular Biology Organization | All Rights Reserved. Source

Pouliot N.,Metastasis Research Laboratory | Pouliot N.,University of Melbourne | Denoyer D.,Deakin University
Cancer Forum | Year: 2014

Cancer progression is characterised by extensive metabolic reprogramming. Renewed enthusiasm in this field has been sparked in part by the realisation that metabolic pathways, oncogenes and tumour suppressors are intimately linked and regulate tumour growth and metastasis through complex reciprocal interactions. The identification of key pathways and enzymes regulating metabolism in cancer cells provides new opportunities for cancer therapy. This has motivated the development of several specific inhibitors targeting metabolic pathways and their therapeutic evaluation in pre-clinical models or in cancer patients. The unravelling of metabolic pathways associated with cancer progression has also highlighted the extensive metabolic heterogeneity that exists between, and within, each cancer type as well as between metastatic sites. The translation of these findings into personalised therapy remains a considerable challenge. To this end, the use of positron emission tomography to non-invasively visualise tumour metabolism is likely to facilitate the implementation of and assessment of new targeted therapies. Here, we briefly review the key metabolic changes associated with cancer progression and discuss recent advances in the field of positron emission tomography for metabolic imaging of cancer and their potential to improve the clinical management of cancer patients. Source

Ooms L.M.,Monash University | Binge L.C.,Monash University | Davies E.M.,Monash University | Rahman P.,Monash University | And 16 more authors.
Cancer Cell | Year: 2015

Metastasis is the major cause of breast cancer mortality. Phosphoinositide 3-kinase (PI3K) generated PtdIns(3,4,5)P3 activates AKT, which promotes breast cancer cell proliferation and regulates migration. To date, none of the inositol polyphosphate 5-phosphatases that inhibit PI3K/AKT signaling have been reported as tumor suppressors in breast cancer. Here, we show depletion of the inositol polyphosphate 5-phosphatase PIPP (INPP5J) increases breast cancer cell transformation, but reduces cell migration and invasion. Pipp ablation accelerates oncogene-driven breast cancer tumor growth in vivo, but paradoxically reduces metastasis by regulating AKT1-dependent tumor cell migration. PIPP mRNA expression is reduced in human ER-negative breast cancers associated with reduced long-term outcome. Collectively, our findings identify PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer. Ooms et al. identify the inositol polyphosphate 5-phosphatase PIPP as a suppressor of oncogenic PI3K/AKT signaling in breast cancer. PIPP depletion increases transformation and accelerates oncogene-driven tumor growth in vivo, while paradoxically reducing cell migration, invasion, and metastasis. © 2015 Elsevier Inc. Source

Wiegmans A.P.,QIMR Berghofer Medical Research Institute | Al-Ejeh F.,QIMR Berghofer Medical Research Institute | Chee N.,QIMR Berghofer Medical Research Institute | Yap P.-Y.,QIMR Berghofer Medical Research Institute | And 9 more authors.
Oncotarget | Year: 2014

In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months. © 2008-2014 Impact Journals, LLC. Source

Ciocca D.R.,CONICET | Cuello-Carrion F.D.,CONICET | Natoli A.L.,Metastasis Research Laboratory | Restall C.,Metastasis Research Laboratory | And 2 more authors.
Histochemistry and Cell Biology | Year: 2012

In a previous study, we measured caveolin-1 protein levels, both in the normal breast and in breast cancer. The study revealed no association between caveolin-1 expression in the epithelial compartment and clinical disease outcome. However, high levels of caveolin-1 in the stromal tissue surrounding the tumor associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her-2/neu expression was accelerated in mice lacking caveolin-1. We have analysed the heat shock protein (Hsp) response in the tumors of mice lacking caveolin-1. In all cases, the mammary tumors were estrogen and progesterone receptor negative, and the levels of Her-2/neu (evaluated by immunohistochemistry) were not different between the caveolin-1 +/+ (n = 8) and the caveolin-1 -/- (n = 7) tumors. However, a significant reduction in the extent of apoptosis was observed in mammary tumors from animals lacking caveolin-1. While Bcl-2, Bax, and survivin levels in the tumors were not different, the amount of HSPA (Hsp70) was almost double in the caveolin-1 -/- tumors. In contrast, HSPB1 (Hsp27/Hsp25) levels were significantly lower in the caveolin-1 -/- tumors. The mammary tumors from caveolin-1 null mice expressed more HSPC4 (gp96 or grp94), but HSPC1 (Hsp90), HSPA5 (grp78), HSPD1 (Hsp60), and CHOP were not altered. No significant changes in these proteins were found in the stroma surrounding these tumors. These results demonstrate that the disruption of the Cav-1 gene can cause alterations of specific Hsps as well as tumor development. © 2011 Springer-Verlag. Source

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