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

Abstract

The thiazolidinediones (TZDs) are a class of synthetic antidiabetic drugs exerting its action primarily upon acti-vation of the peroxisome proliferator-activated receptor-γ (PPARγ). 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 PPARγ by TZDs interferes with oestrogen receptor signalling, STAT5B and NF-κB signalling cascades. On the other hand, TZDs repress TGFβ 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 TGFβ 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 TGFβ signalling and predict influence of TZD exposure on cancer-related clinical outcome.