Transforming growth factor-beta and breast cancer: Mammary gland development

Abstract

Transforming growth factor (TGF)-beta1 is a pluripotent cytokine that profoundly inhibits epithelial proliferation, induces apoptosis, and influences morphogenesis by mediating extracellular matrix deposition and remodeling. The physiologic roles of the action of TGF-beta in mammary gland, indeed in most tissues, are poorly understood. In order to understand the actions of TGF-beta, we need to take into account the complexity of its effects on different cell types and the influence of context on cellular responses. This task is further compounded by multiple mechanisms for regulating TGF-beta transcription, translation, and activity. One of the most significant factors that obscures the action of TGF-beta is that it is secreted as a stable latent complex, which consists of the 24-kDa cytokine and the 80-kDa dimer of its prepro region, called latency-associated peptide. Latency imposes a critical restraint on TGF-beta activity that is often overlooked. The extracellular process known as activation, in which TGF-beta is released from the latent complex, is emphasized in the present discussion of the role of TGF-beta in mammary gland development. Definition of the spatial and temporal patterns of latent TGF-beta activation in situ is essential for understanding the specific roles that TGF-beta plays during mammary gland development, proliferation, and morphogenesis.

Figure 1

Effects of transforming growth factor (TGF)-β in mammary gland. A variety of studies suggest that TGF-β contributes to morphogenesis, growth, and function in mouse mammary gland.

Figure 2

Transforming growth factor (TGF)-β production, secretion, and activation. Some elements of protein processing and post-translation modifications involved in the regulatory control of TGF-β are depicted. The TGF-β¹ gene encodes a 390 amino acid polypeptide that is cleaved into two polypeptides that form homodimers during protein processing: latency-associated peptide (LAP) and TGF-β. These homodimers are noncovalently associated to form the small latent TGF-β complex, which is secreted. Alternatively, this complex can be covalently linked by disulfide bonds to a latent TGF-β binding protein (LTBP) before secretion. LTBP provides means of anchoring latent TGF (LTGF)-β in the extracellular matrix (ECM), which may involve cross-linking by transglutaminase and which requires proteolytic processing to release LTGF-β before activation. Activation occurs extracellularly to release TGF-β at or near the cell surface so that it immediately binds to its receptors. TGF-β receptors I and II form a heterocomplex that signals via the SMAD signal transduction protein family.TGF-β receptor III, also known as betaglycan, is nonsignaling but may be involved in presenting TGF-β to its signaling receptors.

Figure 3

Dual immunolocalization of latency-associated peptide (LAP) and transforming growth factor (TGF)-β in murine mammary gland. Antibodies to LAP (green) to localize latent TGF (LTGF)-β, antigen-purified TGF-β antibodies that specifically detect active TGF-β (red), and DAPI stained nuclei (blue) were visualized using tricolor digital fluorescence microscopy. (A) A section tangential to a duct; (B) a transverse and cross-section of a duct of mammary gland from a nulliparous Balb/c mouse. Colocalization of LAP and TGF-β appears yellow in certain epithelial cells (arrows). Note that certain cells have prominent LAP staining, but are not immunoreactive for TGF-β and are adjacent to cells that exhibit staining of both LAP and TGF-β. Neither stromal, myoepithelial, or endothelial (B, asterisk) cells show prominent TGF-β immunoreactivity.