PMID- 12063559
OWN - NLM
STAT- MEDLINE
DCOM- 20021202
LR  - 20181130
IS  - 1019-6439 (Print)
IS  - 1019-6439 (Linking)
VI  - 21
IP  - 1
DP  - 2002 Jul
TI  - Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene 
      expressing preneoplastic human mammary epithelial cells.
PG  - 127-34
AB  - Aberrant proliferation is an early-occurring event in vitro prior to 
      tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of 
      aberrant proliferation therefore may represent a useful biomarker to evaluate the 
      efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy 
      in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and 
      the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular 
      mechanistic endpoints for chemopreventive effects of retinoids should provide 
      novel biomarkers. The present study was designed to examine the preventive 
      efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic 
      acid (9cisRA), and to identify the possible mechanisms for their effects using 
      the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 
      184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a 
      dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses 
      of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming 
      efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle 
      analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 
      microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M 
      phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold 
      (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent 
      control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) 
      decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two 
      retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. 
      Western blot analysis revealed that ATRA induced an increase in RARbeta 
      expression and a decrease in RARgamma expression, while 9cisRA down-regulated 
      RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit 
      HER-2/neu induced aberrant proliferation in part by retarding cell cycle 
      progression, down-regulating HER-2/neu-mediated signal transduction and inducing 
      Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.
FAU - Jinno, Hiromitsu
AU  - Jinno H
AD  - Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan. 
      jinno@sc.itc.keio.ac.jp
FAU - Steiner, Melissa G
AU  - Steiner MG
FAU - Nason-Burchenal, Kathryn
AU  - Nason-Burchenal K
FAU - Osborne, Michael P
AU  - Osborne MP
FAU - Telang, Nitin T
AU  - Telang NT
LA  - eng
GR  - P01CA29502/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Alitretinoin
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Breast/*metabolism/pathology
MH  - Breast Neoplasms/drug therapy/*metabolism/*prevention & control
MH  - Cell Adhesion
MH  - Cell Cycle/drug effects
MH  - Cell Division/drug effects/genetics
MH  - Dose-Response Relationship, Drug
MH  - Epithelial Cells/drug effects/pathology
MH  - Female
MH  - Gene Expression/drug effects
MH  - Humans
MH  - Proto-Oncogene Proteins c-bcl-2/metabolism
MH  - Receptor, ErbB-2/*metabolism
MH  - Receptors, Retinoic Acid/metabolism
MH  - Tretinoin/*pharmacology
EDAT- 2002/06/14 10:00
MHDA- 2002/12/03 04:00
CRDT- 2002/06/14 10:00
PHST- 2002/06/14 10:00 [pubmed]
PHST- 2002/12/03 04:00 [medline]
PHST- 2002/06/14 10:00 [entrez]
PST - ppublish
SO  - Int J Oncol. 2002 Jul;21(1):127-34.