Retinoids control the expression of c-erbB receptors in breast cancer cells.
Nuclear retinoid and membrane c-erbB receptors participate in signal transduction systems that control mammary epithelial cell proliferation and differentiation. Recently, we demonstrated that c-erbB receptor activation stimulates retinoic acid receptor-alpha expression. We now report that retinoids reduce SK-BR-3 breast cancer cell growth by inhibiting the cell cycle and by inducing apoptosis. This is accompanied with reduced c-erbB expression as determined by FACS, Western, Northern, RT-PCR, and reporter assays. All-trans (ATRA) and 9-cis retinoic acid (9cRA) reduce c-erbB-1 protein to 50-100%, c-erbB-2 to 20-30%, and c-erbB-3 to 10-50% of control, depending on the concentration, respectively, without influencing the tyrosine phosphorylation status. Down-regulation of c-erbB-2 and -3 was seen at all levels analyzed, whereas c-erbB-1 mRNA remained unchanged. Retinoic acid-mediated down-regulation of growth and c-erbB-2 and -3 expression was also seen in MCF-7 cells. We conclude that retinoic acids are efficient repressors of c-erbB-2 and -3 gene expression, whereas c-erbB-1 is not markedly affected.
Offterdinger
M
M
Division of Oncology, Department of Internal Medicine I, University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria.
Schneider
S M
SM
Huber
H
H
Grunt
T W
TW
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D066246:ErbB Receptors / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D018815:Genes, erbB; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D020893:Receptor, ErbB-3; D017978:Receptors, Growth Factor / Q000096:biosynthesis*; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D000077556:Alitretinoin; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017978:Receptors, Growth Factor; D012176:Retinoids; D014212:Tretinoin