Abstract
The main objective of this presentation is to review current knowledge regarding molecular mechanisms of Transforming Growth Factor-?1(TGF-?1) action in breast carcinogenesis. In addition, our recent results will be presented on TGF-?1 gene polymorphism and its relationship to TGF-?1 secretion in breast cancer (BC) patients. Special focus will be made on potential clinical applicability of TGF-?1 as a putative diagnostic, prognostic or predictive tool in BC detection and treatment. TGF-?1 has a complex multifunctional profile, with tumor suppressive effects in early stages of breast carcinogenesis, but progressive dominance of tumor promoting effects with transition to more advanced malignant states. Clarification of molecular mechanisms that control parallel processing of these opposing TGF-?1 activities might suggest new approaches for shifting the balance in favor of net tumor suppression. Now, a major challenge remains in more precisely defining TGF-?1 signaling pathways and their cancer-related alterations. Current dogma views human tumorigenesis as a molecular disruption of normal physiology through genetic, epigenetic, or somatic alterations. The genetic model offers biological plausibility to epidemiological studies that link the TGF-?1 gene polymorphism, at codon 10 due to Leu10Pro substitution in the signal peptide, with the risk of developing BC. The somatic mutations approach, provides an explanation for the TGF-?1 overexpression in advanced BC through mutations acquired in the components of Smad-mediated TGF-?1 signaling pathway. The available results indicate decreased T?RII (TGF-?1 receptor-type II) expression, rare T?RII gene mutations, but no mutations in Smad2 and Smad4 genes, in advanced BC patients. .
Highlights
Despite increased awareness and earlier detection, large percentage of breast cancer (BC) diagnosed women die from metastatic disease each year
Due to the morbidity associated with chemotherapy, there is a demand for molecular markers that can provide a more accurate prognosis and predict response to therapy (2,3)
Special focus will be made on potential clinical applicability of TGF-ß1 as a putative diagnostic, prognostic or predictive tool in BC detection and treatment
Summary
Despite increased awareness and earlier detection, large percentage of breast cancer (BC) diagnosed women die from metastatic disease each year. At the present time Transforming Growth Factor-E1 (TGF-ß1) is being evaluated as potential candidate for such biomarker, its diagnostic role in BC has not been established yet (4) This communication covers literature survey on current knowledge regarding TGF-ß1 molecular mechanisms of action in breast carcinogenesis. Dunning and co-workers (9) have shown that the allele encoding Pro[10] is associated with increased rates of TGF-ß1 secretion in advanced BC patients This and other studies (8) have excluded cases with early stages of BC whose genetic susceptibility might considerably contribute to the evaluation of plasma TGF-ß1 DVDSURJQRVWLFIDFWRUIRUWKH6WDJH,,,GLVHDVH we have investigated the role of plasma TGF-ß1LQSURJQRVLVRIHDUO\ 6WDJH,,, BC patients and possible relevance of genetic variants that affect TGF-ß1 production and secretion. PCR was used to amplify for the TGF-ß1 gene fragment of 485 bp, including the exon 1 and neighbouring parts of the surrounding sequences as described in the Legend to Figure 1
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