- Hovey Laboratory of Mammary Biology. Department of Animal Science, UC Davis
2251 Meyer Hall
One Shields Avenue
Davis, CA 95616-8521
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Role of ErbB receptors in mammary epithelial cells of different animal species and mechanisms regulating ErbB-ligands.
Tutor: Prof Paolo Accornero
The ErbB family of receptors are main players during the normal development of the mammary gland, but also recognized oncogenes in both veterinary and human medicine. The Epidermal Growth Factor Receptor (EGFR/ErbB1) and its ligand Amphiregulin mediate Estrogens (E), inducing the proliferation of mammary epithelium in pubescent mice. However, in pathologic conditions tumorous cells of the mammary epithelium can escape the control of E and become able to self-sustain by what we call an EGFR-dependent autocrine loop. The therapy against ErbB-overexpressing mammary cancers is complicated by the high number or potential combinations between different ErbB receptors and ErbB-ligands. Although most of the research in mammary biology has been conducted on mice, rodents have substantial limitations as models for the human breast: above all, a simpler histoarchitecture and a different hormone regulation. Alternatively, the developing mammary gland of female pigs displays terminal ductal lobular units (TDLU) close to the human TDLUs. We hypothesized that the EGFR-dependent autocrine loop, characterizing several mammary tumors, is the exacerbation of an otherwise normal mechanism of development, independent from E. We also hypothesized that expression pattern and hormonal regulation of ErbB receptors and ligands, in the mammary glands of pubescent pigs, are distinct from those of mice. We have shown that EGFR is expressed by several epithelial cell lines, here used as in vitro model of the physiological mammary epithelium, and that once activated, EGFR triggers a signaling that promotes the proliferation and survival of cells, even in the absence of external stimuli. This proves the existence of an autocrine signal among mammary epithelial cells in vitro. We also proved that ErbB receptors and ligands have a peculiar gene expression pattern and hormonal regulation in the mammary glands of pubescent pigs, with several ErbB factors and ligands other than AREG and EGFR expressed and modulated at epithelial level. The demonstration of an EGFR-dependent autocrine mechanism in vitro, and the distinctive features of ErbB-signaling in more reliable animal model, raised several questions about the mechanisms underneath mammary development during puberty. Emerging differences from the mouse, regarding the role of ErbB and ligands, might help to understand tumorigenic mechanisms in those species characterized by a more complex mammary parenchyma.
- Hormonal regulation of mammary development, with particular interest in the local mediators of systemic hormones.
- ErbB receptors: role in mammary development, mammary cancer and obesity-related mammary conditions.
- Binucleation in the mammary glands of pregnant and lactating animals: distribution, hormonal regulation, implication in lactogenesis.