Genetic control of ductal morphology, estrogen-induced ductal growth, and gene expression in female mouse mammary gland.
The uterotropic response of the uterus to 17β-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous genetic studies from our laboratory using inbred mice that are high (C57BL6/J; B6) or low (C3H/HeJ; C3H) responders to E2 led to the identification of quantitative trait loci (QTL) associated with phenotypic variation in uterine growth and leukocyte infiltration. Like the uterus, phenotypic variation in the responsiveness of the mammary gland to E2 during both normal and pathologic conditions has been reported. In the current experiment, we utilized an E2-specific model of mammary ductal growth combined with a microarray approach to determine the degree to which genotype influences the responsiveness of the mammary gland to E2, including the associated transcriptional programs, in B6 and C3H mice. Our results reveal that E2-induced mammary ductal growth and ductal morphology are genetically controlled. In addition, we observed a paradoxical effect of mammary ductal growth in response to E2 compared with what has been reported for the uterus; B6 is a high responder for the uterus and was a low responder for mammary ductal growth, whereas the reverse was observed for C3H. In contrast, B6 was a high responder for mammary ductal side branching. The B6 phenotype was associated with increased mammary epithelial cell proliferation and apoptosis, and a distinct E2-induced transcriptional program. These findings lay the groundwork for future experiments designed to investigate the genes and mechanisms underlying phenotypic variation in tissue-specific sensitivity to systemic and environmental estrogens during various physiological and disease states.
Department of Medicine (E.H.W., L.K.C., C.T.), University of Vermont, Burlington, Vermont 05405; Receptor Biology (S.C.H.), National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Center for Nuclear Receptors and Cell Signaling (T.N-V., N.R.C., C.T., C-Y.L.), University of Houston, Houston, Texas 77204-5506.
Emma H
EH
Wall
Laure K
LK
Case
Sylvia C
SC
Hewitt
Trang
T
Nguyen-Vu
Nicholes R
NR
Candelaria
Cory
C
Teuscher
Chin-Yo
CY
Lin
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology; D004958:Estradiol / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D008809:Mice, Inbred C3H; D012741:Sexual Maturation / Q000235:genetics*; D014599:Uterus / Q000502:physiology
D050676:Core Binding Factor Alpha 2 Subunit; C493726:Runx1 protein, mouse; D004958:Estradiol