Adipocyte derived paracrine mediators of mammary ductal morphogenesis controlled by retinoic acid receptors.
We generated a transgenic (Tg)-mouse model expressing a dominant negative-(DN)-RARα, (RARαG303E) under adipocytes-specific promoter to explore the paracrine role of adipocyte retinoic acid receptors (RARs) in mammary morphogenesis. Transgenic adipocytes had reduced level of RARα, β and γ, which coincided with a severely underdeveloped pubertal and mature ductal tree with profoundly decreased epithelial cell proliferation. Transplantation experiments of mammary epithelium and of whole mammary glands implicated a fat-pad dependent paracrine mechanism in the stunted phenotype of the epithelial ductal tree. Co-cultures of primary adipocytes, or in vitro differentiated adipocyte cell line, with mammary epithelium showed that when activated, adipocyte-RARs contribute to generation of secreted proliferative and pro-migratory factors. Gene expression microarrays revealed a large number of genes regulated by adipocyte-RARs. Among them, pleiotrophin (PTN) was identified as the paracrine effectors of epithelial cell migration. Its expression was found to be strongly inhibited by DN-RARα, an inhibition relieved by pharmacological doses of all-trans retinoic acid (atRA) in culture and in vivo. Moreover, adipocyte-PTHR, another atRA responsive gene, was found to be an up-stream regulator of PTN. Overall, these results support the existence of a novel paracrine loop controlled by adipocyte-RAR that regulates the mammary ductal tree morphogenesis.
Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA.
Christine V
CV
Marzan
Tara S
TS
Kupumbati
Silvina P
SP
Bertran
TraceyAnn
T
Samuels
Boris
B
Leibovitch
Rafael
R
Mira-y-Lopez
Liliana
L
Ossowski
Eduardo F
EF
Farias
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000637:transplantation; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis / Q000502:physiology*; D019899:Paracrine Communication / Q000502:physiology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology
D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D016207:Cytokines; D017931:DNA Primers; D044168:Receptor, Parathyroid Hormone, Type 1; D018168:Receptors, Retinoic Acid; C066845:pleiotrophin; D014212:Tretinoin