Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland.
As the juvenile mouse mammary gland matures, it undergoes extensive epithelial proliferation, leading to a network of ductal branching that transverses the organ. Recent evidence suggests that the epidermal growth factor-related peptide amphiregulin (AR) may play multiple roles in the proliferation, differentiation, and neoplastic conversion of the mouse mammary gland. Using a dual approach of recombinant AR in slow-release pellets and retroviral expression of AR, we explored the roles of this growth factor in the mouse mammary gland in vivo. We first noted that recombinant AR can reestablish longitudinal ductal proliferation in growth quiescent mammary glands of ovariectomized mice. Furthermore, retrovirally transduced mammary transplants overexpressing AR developed into hyperplastic tertiary ducts and hyperplastic lobules with increased lateral branching, apparent 9 weeks after transplantation into cleared mammary fat pads. This is the first study to demonstrate that AR can reestablish the early developmental activity of ductal mammary epithelium and induce hyperplasia in vivo. These data, coupled with previous findings that demonstrated nearly universal overexpression of AR in human breast cancer and rodent mammary tumorigenesis, suggest that AR may be an important intermediary in glandular maturation and early malignant progression.
Kenney
N J
NJ
Lombardi Cancer Center, Georgetown University, Washington, DC 20007, USA.
Smith
G H
GH
Rosenberg
K
K
Cutler
M L
ML
Dickson
R B
RB
D000273:Adipose Tissue / Q000473:pathology; D066258:Amphiregulin; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D015139:Blotting, Southern; D015153:Blotting, Western; D015197:Carcinogenicity Tests; D017690:Cell Transplantation; D002478:Cells, Cultured / Q000502:physiology / Q000637:transplantation; D066255:EGF Family of Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins; D008321:Mammary Glands, Animal / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000502:physiology; D009368:Neoplasm Transplantation; D010052:Ovariectomy; D012190:Retroviridae; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors
C587848:AREG protein, human; D066258:Amphiregulin; D000970:Antineoplastic Agents; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins