TY - JOUR
T1 - Adipocyte derived paracrine mediators of mammary ductal morphogenesis controlled by retinoic acid receptors
AU - Marzan, Christine V.
AU - Kupumbati, Tara S.
AU - Bertran, Silvina P.
AU - Samuels, Tracey Ann
AU - Leibovitch, Boris
AU - Mira-y-Lopez, Rafael
AU - Ossowski, Liliana
AU - Farias, Eduardo F.
N1 - Funding Information:
We are grateful to Dr. Akira Kakizuka (Kyoto University, Japan) for the gift of pCMX-RAR-E, to Dr. Bruce Spiegelman (Dana-Farber Cancer Institute, Boston, MA) for the PBks-AP2 vector, to Dr. Phillip Scherer (Albert Einstein College of Medicine, NY) for 3T3-L1 cells and to Yeriel Estrada for help with some experiments. This work was supported by the NCI grant CA54273 and the Samuel Waxman Cancer Research Foundation .
PY - 2011/1/15
Y1 - 2011/1/15
N2 - 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.
AB - 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.
KW - Adipocytes
KW - Mammary morphogenesis
KW - Paracrine
KW - Pleiotrophin
KW - RARs
UR - http://www.scopus.com/inward/record.url?scp=78650807244&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2010.10.018
DO - 10.1016/j.ydbio.2010.10.018
M3 - Article
AN - SCOPUS:78650807244
SN - 0012-1606
VL - 349
SP - 125
EP - 136
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -