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

Jarrar MH, Baranova A - J. Cell. Mol. Med. (2007 Jan-Feb)

Bottom Line: The thiazolidinediones (TZDs) are a class of synthetic antidiabetic drugs exerting its action primarily upon activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma).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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Genomics and Bioinformatics, Molecular and Microbiology Department, College of Science, George Mason University, Fairfax, VA, USA.

ABSTRACT
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.

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Related in: MedlinePlus

During the initial phase of breast tumourigenesis, the TGFβ signal inhibits primary tumour development. Eventually, breast carcinoma cells cease to respond to TGFβ due to epigenetic silencing of its receptors or to aberrations in downstream SMAD sig-nalling, causing the switch of TGFβ's role from tumour suppressor to tumour promoter. A crosstalk of PPAR signalling with TGFβ pathway most likely interferes with both functions of this molecule. Most likely, the outcome of the PPAR/TGF crosstalk is defined by the net effects of the TZD-related shifts in the balance of the pro-tumourigenic and tumour suppressor molecules that belong to a number of pathways affected by PPAR.
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fig02: During the initial phase of breast tumourigenesis, the TGFβ signal inhibits primary tumour development. Eventually, breast carcinoma cells cease to respond to TGFβ due to epigenetic silencing of its receptors or to aberrations in downstream SMAD sig-nalling, causing the switch of TGFβ's role from tumour suppressor to tumour promoter. A crosstalk of PPAR signalling with TGFβ pathway most likely interferes with both functions of this molecule. Most likely, the outcome of the PPAR/TGF crosstalk is defined by the net effects of the TZD-related shifts in the balance of the pro-tumourigenic and tumour suppressor molecules that belong to a number of pathways affected by PPAR.

Mentions: Accumulating evidence suggests that the activation of the PPARγ interferes with the propagation of TGFβ signalling and decreases the expression of several genes controlled by this cytokine (Fig. 2). For example, pioglitazone attenuates the TGFβ driven induction of alternatively spliced mRNA and the Extra Domain A (EDA)+ protein isoform of fibronectin that are usually seen in fetal cells, tumour cells, and during wound healing, but not in normal adult cells [93]. Fibronectin molecules with EDA domains are significantly more potent in promoting local cell spread than ‘classical’ fibronectin [94]. EDA-contain-ing fibronectin isoforms are present in up to 47% of breast adenocarcinoma cells and in up to 69% of adjacent stromal cells, but never found in fibroadeno-mas or other benign breast conditions [95]. It is pos-sible that pioglitazone counteracts EDA+ fibronectindependent invasion of breast carcinoma through the suppression of TGFβ-mediated signalling.


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

Jarrar MH, Baranova A - J. Cell. Mol. Med. (2007 Jan-Feb)

During the initial phase of breast tumourigenesis, the TGFβ signal inhibits primary tumour development. Eventually, breast carcinoma cells cease to respond to TGFβ due to epigenetic silencing of its receptors or to aberrations in downstream SMAD sig-nalling, causing the switch of TGFβ's role from tumour suppressor to tumour promoter. A crosstalk of PPAR signalling with TGFβ pathway most likely interferes with both functions of this molecule. Most likely, the outcome of the PPAR/TGF crosstalk is defined by the net effects of the TZD-related shifts in the balance of the pro-tumourigenic and tumour suppressor molecules that belong to a number of pathways affected by PPAR.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401221&req=5

fig02: During the initial phase of breast tumourigenesis, the TGFβ signal inhibits primary tumour development. Eventually, breast carcinoma cells cease to respond to TGFβ due to epigenetic silencing of its receptors or to aberrations in downstream SMAD sig-nalling, causing the switch of TGFβ's role from tumour suppressor to tumour promoter. A crosstalk of PPAR signalling with TGFβ pathway most likely interferes with both functions of this molecule. Most likely, the outcome of the PPAR/TGF crosstalk is defined by the net effects of the TZD-related shifts in the balance of the pro-tumourigenic and tumour suppressor molecules that belong to a number of pathways affected by PPAR.
Mentions: Accumulating evidence suggests that the activation of the PPARγ interferes with the propagation of TGFβ signalling and decreases the expression of several genes controlled by this cytokine (Fig. 2). For example, pioglitazone attenuates the TGFβ driven induction of alternatively spliced mRNA and the Extra Domain A (EDA)+ protein isoform of fibronectin that are usually seen in fetal cells, tumour cells, and during wound healing, but not in normal adult cells [93]. Fibronectin molecules with EDA domains are significantly more potent in promoting local cell spread than ‘classical’ fibronectin [94]. EDA-contain-ing fibronectin isoforms are present in up to 47% of breast adenocarcinoma cells and in up to 69% of adjacent stromal cells, but never found in fibroadeno-mas or other benign breast conditions [95]. It is pos-sible that pioglitazone counteracts EDA+ fibronectindependent invasion of breast carcinoma through the suppression of TGFβ-mediated signalling.

Bottom Line: The thiazolidinediones (TZDs) are a class of synthetic antidiabetic drugs exerting its action primarily upon activation of the peroxisome proliferator-activated receptor-gamma (PPARgamma).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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Genomics and Bioinformatics, Molecular and Microbiology Department, College of Science, George Mason University, Fairfax, VA, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus