Referenced papers were collated from my own personal collection and a previous book called TGFβ and cancer by myself. Further references were identified from searches of MEDLINE and PubMed with the terms “breast cancer”, “transforming growth factor beta”, and “receptor signaling polymorphisms”. Searches were restricted to the past 5 years, and references were selected to provide a balanced and representative overview of a complex subject with an extensive literature base. Only papers
ReviewRole of transforming growth factor β in breast carcinogenesis
Section snippets
Pathobiological models
TGFβ is a component of the complex language of intercellular communication and potentially acts as a switch that permits a biphasic functional profile. In healthy tissues of the developing and adult organism, TGFβ is thought to function mainly as a tumour suppressor via inhibitory growth-factor loops in accordance with the negative autocrine hypothesis, which states that cancer cells themselves can produce and secrete polypeptide growth factors that inhibit their own growth. In the premalignant
Characteristics of TGFβ
TGFβ is a family of multifunctional regulatory peptides involved in a range of processes including development, wound healing, and carcinogenesis.9 It has three mammalian isoforms, each of which is a 25 kDa homodimeric peptide made from two identical peptide chains 112 aminoacids in length. The peptides contain a conserved motif of nine cysteine residues, which form intrachain disulphide bonds together with interchain disulphide bridges linking the peptide monomers into a dimeric structure with
TGF.β receptors
At present, two forms of TGFβ receptor are recognised (type I and type II). They are transmembrane structures with an intracellular component that has intrinsic serine kinase or threonine kinase activity. TGFβ binds to the type-II receptor, which has a constitutively active kinase domain. After binding of the ligand, the phosphorylating activity of the type-II receptor—though increased only slightly—causes a conformational change, leading to recruitment of the type-I receptor into a
Signal transduction pathways
During the past 4–5 years, there have been some important advances in the understanding of postreceptor signal transduction for TGFβ. Generally, these pathways are less complex than expected and involve a finite number of intracellular mediators that convey signals directly from cellsurface receptors to gene transcription sites through nonamplified, stoichiometric pathways.
Smads are a family of intracellular proteins that participate in an evolutionarily conserved signaltransduction pathway
Functions of TGFβ
TGFβ has diverse functions, but it generally inhibits a range of epithelial and endothelial cells and stimulates cells of mesenchymal origin—especially those that synthesise components of the extracellular matrix.2, 27, 28 Additionally, it can induce apoptosis in several types of healthy and transformed cells.29 Furthermore, the broader growthinhibitory effects of TGFβ include decreased cell proliferation and modulation of apoptosis, cellular senescence, and factors that promote genomic
Autocrine growth inhibition
Breast-cancer cell lines both positive and negative for oestrogen receptor (ER) produce and secrete TGFβ isoforms in vitro, and growth of these cells is inhibited by exogenous TGFβ. This finding, together with the widespread distribution of TGFβ receptors, suggests that TGFβ might participate in an autocrine growth-inhibitory loop that involves epithelial cells.
Knabbe and co-workers42 reported that secretion of TGFβ into the conditioned medium of ER-positive MCF7 cells was increased by
Developmental studies
Individual TGFβ isoforms are expressed differentially throughout development of the mammary glands, and their roles are determined by specific patterns of spatial and temporal localisation.3 In mice, exogenous TGFβ1 administered as slow-release implants can induce striking regression of the proliferating stem-cell layer of end buds, with concomitant involution and resultant inhibition of ductal growth in the developing mammary gland.56 These inhibitory effects on duct elongation occur only when
Transgenic studies
Valuable insight into the potential role of TGFβ isoforms in vivo has been gained from studies with transgenic models, in which a selected protein is either not expressed (ie, loss of function) or is overexpressed (ie, gain of function) in target tissues.6 To some extent, these approaches overcome the issue of context dependency, although TGFβ protein might be expressed in very high concentrations and by a different cell type. Furthermore, functional redundancy might compensate for the loss of
Stage of tumour development
The stage of carcinogenesis must be taken into account in assessment of the role of TGFβ in tumour progression and the response to therapeutic interventions in breast cancer. In healthy tissue, premalignant, and early-transformed states, TGFβ might act mainly as an epithelial growth inhibitor. Epithelial cells and stromal cells might produce and secrete this inhibitory factor, which can potentially act in either an autocrine or a paracrine way. As cells progress along the neoplastic continuum,
Therapeutic perspectives
There is evidence for the preservation of functional TGFβ growth-inhibitory loops in the early stages of malignant transformation. The growth-inhibitory effects of TGFβ could be harnessed at a stage in carcinogenesis in which subtle shifts in the balance of growth factors can determine epithelial-cell behaviour and proliferative potential. The functional augmentation of both autocrine and paracrine inhibitory loops by pharmacological agents allows the exploitation of natural biological
Conclusions
TGFβ has a complex multifunctional profile, with growthinhibitory effects in early stages of breast carcinogenesis, but progressive dominance of oncogenic effects with transition to more advanced malignant states. Therapeutic endeavours should focus on the exploitation of growth-inhibitory properties, with development of specifically designed drugs with more potent and specific effects on the synthesis, secretion, and bioavailability of TGFβ.
Clarification of the mechanisms that control parallel
Search strategy
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