title: A humanized pattern of aromatase expression is associated with mammary hyperplasia in mice.
abstract: Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Arom(hum) mice were higher than in wild-type mice, whereas circulating levels were similar. Arom(hum) mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies.
authors.affiliation: Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. h-zhao@northwestern.edu
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Pearson
authors.forename: David C
authors.initials: DC
authors.lastname: Brooks
authors.forename: John S
authors.initials: JS
authors.lastname: Coon
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Masashi
authors.initials: M
authors.lastname: Demura
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Charles V
authors.initials: CV
authors.lastname: Clevenger
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Robert T
authors.initials: RT
authors.lastname: Chatterton
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D004967:Estrogens / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010053:Ovary / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013997:Time Factors
chemical_list: D004967:Estrogens; D050799:STAT5 Transcription Factor; D001141:Aromatase