Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis - PubMed (original) (raw)

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Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis

J W Pollard. Breast Cancer Res. 2001.

Abstract

The mammary gland undergoes morphogenesis through the entire reproductive life of mammals. In mice, ductal outgrowth from the nipple across the fat pad results in an intricate, well spaced ductal tree that further ramifies and develops alveolar structures during pregnancy. Ductal morphogenesis is regulated by the concerted action of circulating steroid and polypeptide hormones, and local epithelial-mesenchymal inductive signals. Transforming growth factor (TGF)-beta1-3 and hepatocyte growth factor (HGF)/scatter factor (SF) are important components of this latter signaling pathway. TGF-beta1 and TGF-beta3 have roles in both promotion and inhibition of branching morphogenesis that are dependent on concentration and context. HGF/SF promotes ductal outgrowth and tubule formation in the mammary gland. These data suggest that these two growth factors have complementary roles in promoting mammary ductal morphogenesis and in maintaining ductal spacing. In addition, TGF-beta3 triggers apoptosis in the alveolar epithelia, which is a necessary component of mammary gland involution and return of the ductal structure to a virgin-like state after lactation.

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Figures

Figure 1

Schematic of the TGF-β signaling pathway, showing the activation cascade and points of inhibition (??). Active TGF-β, released from the latent complex by the action of thrombospondin, binds to the type II receptor, resulting in the formation of an active receptor-signaling complex. This binding is enhanced by accessory receptors, whereas the receptor dimerization can be inhibited by membrane-bound inhibitors such as bone morphogenic protein and activin membrane bound inhibitor (BAMBI). After ligand binding, the receptor SMADs are phosphorylated, dimerize with SMAD-4, and translocate to the nucleus where they recruit appropriate cofactors and coactivators to stimulate transcription of target genes. TGF-β signaling can be blocked by the inhibitory SMADs, SMAD-6 and SMAD-7, which prevent receptor-SMAD activation; and by the ras pathway, which can lead to inhibition of nuclear translocation of the dimeric SMAD complex. Receptor SMADs can also be degraded following ubiquinylation by the ubiquitin ligase SMURF1. Figure adapted from Massagué [5].

Figure 2

Postulated roles for TGF-β and HGF/SF during the life cycle of the mammary gland. TGF-βs have complex roles during mammary development, according to their concentration. Although most of the experimental evidence points to inhibition of ductal branching, preliminary analysis of both TGF-β1- and SMAD-3-null mutant mice suggest a requirement for TGF-β1 for mammary development. Thus, TGF-βs have both concentration- and context-dependent effects on mammary gland development. HGF/SF promotes ductal outgrowth through an integrin-mediated process. This action is inhibited by TGF-β1, indicating that interactions between these growth factors play a role in ductal spacing as the mammary gland grows out over the fat pad. During pregnancy, TGF-βs appear to inhibit alveolar development and suppress milk formation. The decline in TGF-β expression at the end of pregnancy appears to be necessary for full lobuloalveolar development and lactation. After weaning involution is begun, with TGF-β3 inducing apoptosis in the lobuloalveolar structures through an autocrine mechanism.

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Tumour-stromal interactions. Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis - PubMed (original) (raw)