Expression and functional properties of transforming growth factor alpha and epidermal growth factor during mouse mammary gland ductal morphogenesis.

Abstract

Expression and functional properties of transforming growth factor a and epidermal growth factor during mouse mammary gland ductal morphogenesis ( Communicated by Elwood V. Jensen, October 1, 1990ABSTRACT Primer-directed enzyme amplification was used to examine epidermal growth factor (EGF) and transforming growth factor a (TGF-a) mRNA transcripts in mammary glands of young virgin, mature virgin, midpregnant, and midlactating mice. Transcripts for both EGF and TGF-a mRNA were detected in virgin and pregnant mice, whereas transcripts for EGF mRNA but not TGF-a mRNA were expressed in 10-day lactating mice. TGF-a was localized in the epithelial cap-cell layer of the advancing terminal end bud and in the stromal fibroblasts at the base of the terminal end bud; EGF was localized in the inner layers of the terminal end bud and in ductal cells of mammary epithelium. Implantation of pellets containing EGF or TGF-a into the regressed mammary gland of ovariectomized mice stimulated the reappearance of end buds; contralateral glands implanted with pellets containing albumin or insulin were not affected. These results indicate that an EGF-receptor-mediated pathway remained intact in the mammary gland epithelium in the absence of ovarian steroids and that local availability of either EGF or TGF-a is sufficient to stimulate the pattern of normal ductal growth. The detection of EGF and TGF-a transcripts at different stages of mammary gland development and the different patterns of immunolocalization suggest that each polypeptide plays a different role in normal mammary gland morphogenesis.Unlike other organ systems, most of the development of mouse mammary gland occurs postnatally. Before onset of ovarian function, the postnatal mouse mammary gland consists of a primary duct and a few primitive branched ducts emanating from the nipple (Fig. 1A) (1, 2). Ovarian secretion of estrogens at about 4 weeks of age stimulates rapid ductal growth in the mouse mammary gland (1, 3) and the formation of bulbous, multicell layered terminal end buds (TEBs) that serve as growth points for elongation and branching of the ducts through the fatty stroma (Fig. 1B) (2-5). The growing ductal tree extends to fill the fat pad (Fig. 1C) and when the gland reaches the limits of the fat pad at 12-14 wk of age (Fig. 1D), the TEBs disappear (5, 6).Estrogens are thought to directly stimulate mammary ductal morphogenesis by interaction with specific receptors in the gland (7,8). The steps that succeed mammary gland estrogen-receptor binding and ultimately lead to cell proliferation have not been identified. Estrogens may stimulate cell division through an autocrine or paracrine mechanism (9) by stimulating the production of a peptide growth factor. Particular attention has been given to an autocrine role of transforming growth factor a (TGF-a) because expression of this growth factor has been identified in breast tumors (10,11) and derived cell lines (11,12). TGF-a is a 50-amino acid mitogenic polypeptide that is structurally and biologically homologous to...

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

“…Although the above genetic evidence indicates that AREG is uniquely required for normal mammary morphogenesis [25], other studies had shown that several EGFR ligands could rescue ductal development in ovariectomized and ERα-deficient mice [26,[31][32][33] and that all EGFR ligands had comparable effects in culture [17,28]. So why were other EGFR agonists unable to compensate for the absence of AREG in vivo?…”

Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

“…Signal transduction from the EGFR is initiated when ligand binding stimulates receptor dimerization and tyrosine autophosphorylation on multiple carboxy-terminal tyrosines, which then act as high-affinity binding sites for effector proteins [25]. EGFR signaling pathways regulate proliferation of normal mammary epithelial cells [26][27][28] and of ER(+) hormone-dependent HBC cells [29].…”

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

“…Similar cellular and temporal expression patterns have been documented for EGFR (DiAugustine et al, 1997;Ederly et al, 1985;Sebastian et al, 1998;Schroeder and Lee, 1998), ErbB3 (Sebastian et al, 1998;Schroeder and Lee, 1998;Yang et al, 1995), and ErbB4 (Sebastian et al, 1998;Yang et al, 1995), although the expression of ErbB4 is highest during pregnancy (Schroeder and Lee, 1998). Likewise, the EGFR agonists, EGF (Schroeder and Lee, 1998;Snedeker et al, 1991), TGFa (Schroeder and Lee, 1998;Snedeker et al, 1991), and AR (Kenney et al, 1995;Schroeder and Lee, 1998) are expressed in both virgin and pregnant mammary tissue. In contrast to these ligands, signi®cant expression levels of the ErbB3 and ErbB4 ligand, NRG1, are only detected during pregnancy (Yang et al, 1995).…”

“…Mammary implants containing EGF (Coleman et al, 1988;Snedeker et al, 1991), TGFa (Snedeker et al, 1991), or AR (Kenney et al, 1996) induce ductal morphogenesis and proliferating terminal end bud (TEB) formation in ovariectomized mice. Consistent with the proliferative e ects of EGFR ligands on mammary development, inhibition of EGFR signaling with a dominant negative EGFR results in decreased ductal proliferation and impaired morphogenesis in the virgin mammary gland (Xie et al, 1997).…”