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Available from: ije.oxfordjournals.org
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ABSTRACT: Cellular senescence entails an irreversible cell-cycle arrest characterised by drastic cytomorphological and metabolic changes. In recent years, the implications of cellular senescence in physiological and pathological settings, such as ageing and cancer, have gained firm ground. It is, therefore, important to understand the mechanisms underpinning the establishment and maintenance of senescence. Age-dependent alterations in cellular metabolic processes are greatly driven by changes in mitochondrial function and homeostasis. Classically, mitochondrial dysfunction has been implicated in cellular senescence mainly by promoting oxidative damage-induced cell-cycle arrest; however, emerging data suggests that other mitochondrial-dependent factors play an important role in the induction of senescent phenotypes. Here we review the role of mitochondrial homeostatic mechanisms, mitochondrial metabolites and ROS generation in the signalling pathways leading to the induction and maintenance of cellular senescence and discuss how this may contribute to the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Copyright © 2015. Published by Elsevier B.V.
Available from: PubMed Central
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ABSTRACT: Stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. Study aims were to: validate microarray studies that demonstrate TFF3 regulation by oestrogen and association with oestrogen receptor in breast cancer, evaluate TFF3 as a biomarker of endocrine response, and investigate TFF3 function. Microarray data were validated by quantitative RT-PCR, northern and western transfer analyses. TFF3 was induced by oestrogen and its induction inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. Expression of TFF3 and oestrogen receptor mRNAs was associated in breast tumours (Pearson's coefficient=0.762; p=0.000). Monoclonal antibodies raised against TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree and duration of response in unstratified metastatic breast cancer patients (p=0.000; p=0.002; p=0.002). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and of degree of response and was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker possibly because it mediates malign effects of oestrogen on invasion and metastasis.
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