Scatchard analyses of the binding of transforming growth factor-beta (TGF-beta) to a wide variety of different cell types in culture revealed the universal presence of high affinity (Kd = 1-60 pM) receptors for TGF-beta on every cell type assayed, indicating a wide potential target range for TGF-beta action. There was a strong (r = +0.85) inverse relationship between the receptor affinity and the number of receptors expressed per cell, such that at low TGF-beta concentrations, essentially all cells bound a similar number of TGF-beta molecules per cell. The binding of TGF-beta to various cell types was not altered by many agents that affect the cellular response to TGF-beta, suggesting that modulation of TGF-beta binding to its receptor may not be a primary control mechanism in TGF-beta action. Similarly, in vitro transformation resulted in only relatively small changes in the cellular binding of TGF-beta, and for those cell types that exhibited ligand-induced down-regulation of the receptor, down-regulation was not extensive. Thus the strong conservation of binding observed between cell types is also seen within a given cell type under a variety of conditions, and receptor expression appears to be essentially constitutive. Finally, the biologically inactive form of TGF-beta, which constitutes greater than 98% of autocrine TGF-beta secreted by all of the twelve different cell types assayed, was shown to be unable to bind to the receptor without prior activation in vitro. It is proposed that this may prevent premature interaction of autocrine ligand and receptor in the Golgi apparatus.

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Distribution and modulation of the cellular receptor for transforming growth factor-beta.

Overexpression of the receptor tyrosine kinase ErbB2/HER2/Neu (ErbB2) occurs in 15-40% of human breast cancers. To determine the function of ErbB2 signaling during normal mouse mammary gland development, we expressed a carboxyl-terminal truncated dominant negative allele of ErbB2 (ErbB2deltaIC) in the developing mouse mammary gland. Despite ErbB2deltaIC expression within mammary glands of pubescent virgin and pregnant mice, a phenotype was not observed until late in pregnancy. At 1 day post-partum, lactationally active, distended lobuloalveoli failed to form. This phenotype was exaggerated in multiparous females expressing ErbB2deltaIC. Immunohistochemical staining for ErbB2deltaIC revealed a concordance between high levels of ErbB2deltaIC protein expression and the absence of lactational products within the lumens of ErbB2deltaIC stained lobuloalveoli. These results demonstrate that ErbB2 signaling is required for proper mammary development and lactation at parturition.

Expression of dominant-negative ErbB2 in the mammary gland of transgenic mice reveals a role in lobuloalveolar development and lactation.

Prolactin (PRL) regulates the development of the mammary gland at three stages in the reproductive life history of females. The first stage is mammary gland organogenesis, during which PRL contributes to the maturation of the mammary glands from a primary ductal system, which grows from terminal end buds, to the fully mature nonpregnant gland. The mature mammary gland is characterized by an absence of terminal end buds, and the development of a highly branched architecture, which is decorated by lobular buds. During pregnancy PRL, placental lactogens, and progesterone stimulate the expansion and physiological differentiation of the lobuloalveolar system from the lobular buds. After delivery PRL, in the context of falling progesterone, stimulates the final induction of milk protein gene expression and lactation. PRL acts directly on the mammary epithelium, and indirectly by stimulating luteal progesterone secretion in rodents. Disruption of the genes for PRL and the PRL receptor, as well as those for transcription factors important in mammary gland regulation (Stat proteins), have provided a new set of animal models with which to study normal mammary gland development and the relationships of PRL to breast carcinogenesis. Two major deficiencies in our current knowledge of PRL actions are our understanding of the role of epithelial-stromal interactions in PRL-induced mammary morphogenesis, and the identity of developmentally important genes that are regulated by PRL during normal mammary gland organogenesis.

Prolactin and mammary gland development.

During the life cycle of a female mammal, the mammary glands (or breasts) undergo a dramatic series of cyclical changes. The glands must first undergo morphogenesis to prepare for pregnancy-induced lactogenesis, followed by lactation and involution. This cycle continues and repeats with each subsequent pregnancy. Brief periods of cyclic growth and regression of the epithelial component of the gland occur during the estrous or menstrual cycle in the adult female’s nonpregnant intervals.

Regulation of development of the normal mammary gland by hormones and growth factors.

Publisher Summary This chapter focuses on the role of epidermal growth factor (EGF) and transforming growth factor type α (TGF-α) in organogenesis in mouse. It discusses EGF and the related growth factor, transforming growth factor type α (TGF-α) and also discusses specific morphogenetic events in which EGF/TGF-α may participate and that involve epithelial-mesenchymal interactions. There is a substantial amount of evidence that EGF-like growth factors have a physiological role in organ development and that the action of EGF or TGF-α in the development of epithelial-mesenchymal organs is associated with tissue interactions that guide morphogenesis and differentiation. EGF and TGF-α act as paracrine mediators of tissue interactions during organ development, as has been suggested for TGF-α, which, together with fibroblast growth factor, acts as a morphogen to induce differentiation of embryonic tissue that is normally induced by tissue interactions.

Epidermal growth factor and transforming growth factor-alpha in the development of epithelial-mesenchymal organs of the mouse.

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Carlo M. Veneziale

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Control of cell growth and proliferation