Myoepithelial and luminal breast cancer cells exhibit different responses to all-trans retinoic acid

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• 作者：Damián E. Berardi ; Carolina Flumian ; Paola B. Campodónico…
• 关键词：Mammary cancer ; Retinoic acid receptors ; Luminal and myoepithelial cells ; EMT
• 刊名：Cellular Oncology
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：38
• 期：4
• 页码：289-305
• 全文大小：5,412 KB
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• 作者单位：Damián E. Berardi (1)
  Carolina Flumian (1)
  Paola B. Campodónico (1) (5)
  Alejandro J. Urtreger (1) (2)
  María I. Diaz Bessone (1)
  Andrea N. Motter (3)
  Elisa D. Bal de Kier Joffé (1) (2)
  Eduardo F. Farias (4)
  Laura B. Todaro (1) (2)
  
  1. Research Area, Institute of Oncology “Angel H. Roffo- University of Buenos Aires, Av. San Martín 5481, C1417DTB, Buenos Aires, Argentina
  5. Genzyme de Argentina S.A., Buenos Aires, Argentina
  2. Member of the Scientific Research Career of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
  3. Scientific Coordination (CC) Operative Unit, Biological Containment Center (UOCCB) ANLIS “Dr. Carlos G. Malbrán- Buenos Aires, Argentina
  4. Division of Hematology-Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  
• 刊物主题：Cancer Research; Biomedicine general; Pathology; Oncology;
• 出版者：Springer Netherlands
• ISSN：2211-3436

文摘

Purpose Breast cancer is the leading cause of death among women worldwide. The exact role of luminal epithelial (LEP) and myoephitelial (MEP) cells in breast cancer development is as yet unclear, as also how retinoids may affect their behaviour. Here, we set out to evaluate whether retinoids may differentially regulate cell type-specific processes associated with breast cancer development using the bi-cellular LM38-LP murine mammary adenocarcinoma cell line as a model. Materials and methods The bi-cellular LM38-LP murine mammary cell line was used as a model throughout all experiments. LEP and MEP subpopulations were separated using inmunobeads, and the expression of genes known to be involved in epithelial to mysenchymal transition (EMT) was assessed by qPCR after all-trans retinoic acid (ATRA) treatment. In vitro invasive capacities of LM38-LP cells were evaluated using 3D Matrigel cultures in conjunction with confocal microscopy. Also, in vitro proliferation, senescence and apoptosis characteristics were evaluated in the LEP and MEP subpopulations after ATRA treatment, as well as the effects of ATRA treatment on the clonogenic, adhesive and invasive capacities of these cells. Mammosphere assays were performed to detect stem cell subpopulations. Finally, the orthotopic growth and metastatic abilities of LM38-LP monolayer and mammosphere-derived cells were evaluated in vivo. Results We found that ATRA treatment modulates a set of genes related to EMT, resulting in distinct gene expression signatures for the LEP or MEP subpopulations. We found that the MEP subpopulation responds to ATRA by increasing its adhesion to extracellular matrix (ECM) components and by reducing its invasive capacity. We also found that ATRA induces apoptosis in LEP cells, whereas the MEP compartment responded with senescence. In addition, we found that ATRA treatment results in smaller and more organized LM38-LP colonies in Matrigel. Finally, we identified a third subpopulation within the LM38-LP cell line with stem/progenitor cell characteristics, exhibiting a partial resistance to ATRA. Conclusions Our results show that the luminal epithelial (LEP) and myoephitelial (MEP) mammary LM38-P subpopulations respond differently to ATRA, i.e., the LEP subpopulation responds with increased cell cycle arrest and apoptosis and the MEP subpopulation responds with increased senescence and adhesion, thereby decreasing its invasive capacity. Finally, we identified a third subpopulation with stem/progenitor cell characteristics within the LM38-LP mammary adenocarcinoma cell line, which appears to be non-responsive to ATRA.