Amphiregulin is an essential mediator of estrogen receptor alpha function in mammary gland development.
Most mammary gland development occurs after birth under the control of systemic hormones. Estrogens induce mammary epithelial cell proliferation during puberty via epithelial estrogen receptor alpha (ERalpha) by a paracrine mechanism. Epidermal growth factor receptor (EGFR) signaling has long been implicated downstream of ERalpha signaling, and several EGFR ligands have been described as estrogen-target genes in tumor cell lines. Here, we show that amphiregulin is the unique EGF family member to be transcriptionally induced by estrogen in the mammary glands of puberal mice at a time of exponential expansion of the ductal system. In fact, we find that estrogens induce amphiregulin through the ERalpha and require amphiregulin to induce proliferation of the mammary epithelium. Like ERalpha, amphiregulin is required in the epithelium of puberal mice for epithelial proliferation, terminal end buds formation, and ductal elongation. Subsequent stages, such as side-branching and alveologenesis, are not affected. When amphiregulin(-/-) mammary epithelial cells are in close vicinity to wild-type cells, they proliferate and contribute to all cell compartments of the ductal outgrowth. Thus, amphiregulin is an important paracrine mediator of estrogen function specifically required for puberty-induced ductal elongation, but not for any earlier or later developmental stages.
Ciarloni
Laura
L
Swiss Institute for Experimental Cancer Research, National Center of Competence in Research, Molecular Oncology, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Mallepell
Sonia
S
Brisken
Cathrin
C
D066258:Amphiregulin; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D004847:Epithelial Cells / Q000166:cytology; D066246:ErbB Receptors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013997:Time Factors
D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D066246:ErbB Receptors