Localization of recognition site between transforming growth factor-beta(1) (TGF-beta(1)) and TGF beta receptor type II: possible implications in breast cancer
Dimitrijević, Bogomir B.
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Although overexpression of TGF-beta(1) protein has been demonstrated in advanced breast cancer(BC) patients, as well as in other solid tumours, the molecular mechanism of this process remains obscure. This paper proposes that a genetic/epigenetic alteration might occur in the TGF-beta(1) gene, within the region coding for the recognition site with TGF(beta) receptor type II, leading to a disruption of the ligand-receptor interaction and triggering the TGF-beta(1) cascade-related BC progression. To establish the operational framework for this hypothesis, in the present study, this recognition site was identified by the Informational Spectrum Method (ISM) to comprise two TGF-beta(1) peptides (positions 47-66 as and 83-112 aa) and one receptor peptide at positions 112-151 as of the extracellular domain of the receptor (TbetaRII(M)). The TbetaRII(M) locus was further evaluated by ISM-derived deletion analysis of the TbetaRII sequences. To provide experimental support for the proposed model..., a pilot study of plasma TGF-beta(1) analysis was performed in advanced BC patients (n = 8). Two commercial ELISA assays, one with specific alphaTGF-beta(1) MAb (MAb) and other with TbetaRII(M) as the immobilized phase, revealed pronounced differences in the pattern of plasma TGF-beta(1) elevation. In MAb-profile, the TGF-beta(1) increase was detected in 7 of 8 patients, whereas analogous TbetaRII(M)-profile revealed the elevation in 3 of 8 patients, taking a 50% of maximal elevation as the cut-off value. These findings are consistent with the proposed aberration of TGF-beta(1) ligand within the TbetaRII recognition site. Summarizing, this model system is a good starting point for further genetic studies, particularly on genetic/epigenetic alterations of sequences involved in TGF-beta(1) and TbetaRII(M) interaction, with putative prognostic value for breast cancer. (C) 2004 Elsevier Ltd. All rights reserved.