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Retinoids control the expression of c-erbB receptors in breast cancer cells
M Offterdinger1, S M Schneider, H Huber
1Division of Oncology, Department of Internal Medicine I, University of Vienna, Waehringer Guertel 18-20, Vienna, A-1090, Austria.
Abstract:
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.
Insights
Retinoids, including all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9cRA), inhibit breast cancer cell growth by reducing c-erbB receptor expression. These findings highlight retinoids as potential therapeutic agents targeting c-erbB signaling in cancer.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Nuclear retinoid and membrane c-erbB receptors are crucial in mammary epithelial cell proliferation and differentiation.
- Previous studies showed c-erbB receptor activation upregulates retinoic acid receptor-alpha expression.
Purpose of the Study:
- To investigate the effect of retinoids on breast cancer cell growth and c-erbB receptor expression.
- To determine the impact of retinoids on cell cycle and apoptosis in breast cancer cells.
Main Methods:
- SK-BR-3 and MCF-7 breast cancer cell lines were treated with all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9cRA).
- Cell growth, cell cycle, apoptosis, and c-erbB receptor expression (c-erbB-1, -2, -3) were analyzed using FACS, Western blot, Northern blot, RT-PCR, and reporter assays.
Main Results:
- Retinoids significantly reduced SK-BR-3 cell growth by inhibiting the cell cycle and inducing apoptosis.
- Retinoids decreased c-erbB-1, c-erbB-2, and c-erbB-3 protein levels, with notable down-regulation of c-erbB-2 and -3 at both mRNA and protein levels.
- Retinoic acid-mediated down-regulation of growth and c-erbB-2 and -3 expression was also observed in MCF-7 cells.
Conclusions:
- Retinoic acids effectively repress c-erbB-2 and c-erbB-3 gene expression in breast cancer cells.
- Retinoids demonstrate potential as therapeutic agents by inhibiting cancer cell proliferation through modulation of c-erbB signaling pathways.