title: A clinically relevant bi-cellular murine mammary tumor model as a useful tool for evaluating the effect of retinoic acid signaling on tumor progression.
abstract: BACKGROUND
  The effect of retinoic acid (RA) on breast cancer progression is controversial. Our objective was to obtain information about breast cancer progression, taking advantage of the ER-negative murine mammary adenocarcinoma model LM38 (LM38-LP constituted by luminal (LEP) and myoepithelial-like cells (MEP), LM38-HP mainly composed of spindle-shaped epithelial cells, and LM38-D2 containing only large myoepithelial cells), and to validate the role of the retinoic acid receptors (RARs) in each cell-type compartment.
  
  
  METHODS
  We studied the expression and functionality of the RARs in LM38 cell lines. We analyzed cell growth and cell cycle distribution, apoptosis, the activity of proteases, motility properties, and expression of the molecules involved in these pathways. We also evaluated tumor growth and dissemination in vivo under retinoid treatment.
  
  
  RESULTS
  LM38 cell lines expressed most retinoic receptor isotypes that were functional. However, only the bi-cellular LM38-LP cells responded to retinoids by increasing RARβ2 and CRBP1 expression. The growth of LM38 cell sublines was inhibited by retinoids, first by inducing arrest in MEP cells, then apoptosis in LEP cells. Retinoids induced inhibitory effects on motility, invasiveness, and activity of proteolytic enzymes, mainly in the LM38-LP cell line. In in-vivo assays with the LM38-LP cell line, RA treatment impaired both primary tumor growth and lung metastases dissemination.
  
  
  CONCLUSIONS
  These in-vivo and in-vitro results show that to achieve maximum effects of RA on tumor progression both the LEP and MEP cell compartments have to be present, suggesting that the interaction between the LEP and MEP cells is crucial to full activation of the RARs.
authors.affiliation: Research Area, Institute of Oncology "Angel H. Roffo", University of Buenos Aires, 5481 San Martín Ave, C1417DTB, Buenos Aires, Argentina.
authors.forename: Laura Beatriz
authors.initials: LB
authors.lastname: Todaro
authors.forename: María José
authors.initials: MJ
authors.lastname: Veloso
authors.forename: Paola Bernadette
authors.initials: PB
authors.lastname: Campodónico
authors.forename: Lydia Inés
authors.initials: LI
authors.lastname: Puricelli
authors.forename: Eduardo Francisco
authors.initials: EF
authors.lastname: Farías
authors.forename: Elisa Dora
authors.initials: ED
authors.lastname: Bal de Kier Joffé
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C082927:retinoic acid binding protein I, cellular; C540966:retinoic acid receptor, beta2, human; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases