PPARgamma activation by thiazolidinediones (TZDs) may modulate breast carcinoma outcome: the importance of interplay with TGFbeta signalling

The thiazolidinediones (TZDs) are a class of synthetic antidiabetic drugs exerting its action primarily upon activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma). Given the widespread incidence of diabetes type II and lifelong exposure of these patients to TZDs, there is a...

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Bibliographic Details
Published in:Journal of cellular and molecular medicine 2007-01, Vol.11 (1), p.71-87
Main Authors: Jarrar, Mohammed H, Baranova, Ancha
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Carcinoma - drug therapy
Disease Models, Animal
Female
Forecasting
Humans
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
Mammary Neoplasms, Animal - drug therapy
Mammary Neoplasms, Animal - metabolism
Models, Biological
PPAR gamma - metabolism
Signal Transduction
Thiazolidinediones - pharmacology
Thiazolidinediones - therapeutic use
Transforming Growth Factor beta - metabolism
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Summary:The thiazolidinediones (TZDs) are a class of synthetic antidiabetic drugs exerting its action primarily upon activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma). Given the widespread incidence of diabetes type II and lifelong exposure of these patients to TZDs, there is a possibility that chronic treatment with TZD modifies clinical phenotypes of other common human diseases, for example breast carcinoma. There is evidence that TZDs act as breast carcinoma suppression agents, at least in the in vitro and animal models. Stimulation of the PPARgamma by TZDs interferes with oestrogen receptor signalling, STAT5B and NF-kappaB signalling cascades. On the other hand, TZDs repress TGFbeta signalling, a well-known suppressor of the initial stages of breast carcinoma development. Another layer of complexity arises at the later stages of tumour development, when TGFbeta acts as a tumour promoter: its overexpression is associated with poor prognosis, higher degree of tumour vascularization and metastasis. Longitudinal studies of breast carcinoma development in chronic TZD users are needed. In this review, we dissect possible interplays between chronic exposure of breast tis-sue to TZDs and TGFbeta signalling and predict influence of TZD exposure on cancer-related clinical outcome.
ISSN:1582-1838