An in vivo study of Cdh1/APC in breast cancer formation.
Dysregulation of the ubiquitin-proteasome system (UPS) has been implicated in several types of tumorigenesis. Our previous studies have shown the potential role of Cdh1/APC in regulating tumor formation via governing the Skp2-p27-cyclinE/CDK2 axis. In this work, we used a xenograft mouse breast cancer model to identify the mechanism by which Cdh1/APC potentially suppresses tumor growth in vivo. Here, we report that depletion of Cdh1 results in a significant enhancement of the breast tumor proliferation, while elevated Cdh1 leads to suppression of breast tumor growth. Analysis of breast tissue arrays has indicated that higher levels of Cdh1 are associated with normal breast epithelial tissues whereas lower Skp2 expression and elevated p27 levels are detected. Conversely, the percentage of breast cancer tissues stained positive for Cdh1 and p27 are significantly lower with higher Skp2 levels. Thus, the E3 ligase, Cdh1/APC, may inhibit breast tumor growth via regulating Skp2-p27 mediated cell cycle progression.
Fujita
Takeo
T
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Liu
Weijun
W
Doihara
Hiroyoshi
H
Wan
Yong
Y
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D015820:Cadherins / Q000502:physiology*; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000494:pharmacology; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; C513384:CDH1 protein, human; C436291:CDKN1B protein, human; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome