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Decrease of c-erbB-2 and c-myc RNA levels in tamoxifen-treated breast cancer
X Le Roy1, C Escot, J P Brouillet
1INSERM Unité Hormones et Cancer (U148), Montpellier, France.
Abstract:
The c-myc, c-erbB-2, hst and int-2 oncogenes are frequently amplified and/or overexpressed in human breast carcinomas. We studied the effect of tamoxifen on RNA levels of these oncogenes in 19 breast cancer patients treated for 3 weeks prior to surgery as compared with 22 control patients. RNA levels were measured by in situ hybridization coupled with computer-aided quantification. c-myc and c-erbB-2 expression was high in the control population (mean values: 23.4 and 29.1 grains/cell respectively) and significantly decreased in the tamoxifen-treated population (mean values: 14.6 and 7.4 grains/cell respectively) (P = 0.018, P = 0.003 respectively); hst and int-2 RNA levels were low (2-6 grains/cell) and not significantly altered by the treatment. There was a correlation between gene amplification and expression for c-erbB-2 (P = 0.0005) and hst (P = 0.02) in the control population. Elevated c-erbB-2 RNA level was correlated with the absence of estrogen (P = 0.02) or progesterone (P = 0.05) receptors. In the ER+ population, the tamoxifen-treated group had significantly lower c-myc expression levels than the control group (P = 0.04) which is in agreement with the estrogen induction of c-myc in ER+ T47D cell line and its inhibition by antiestrogens. Surprisingly, c-erbB-2 expression in the tamoxifen-treated group was significantly diminished in the ER- (P = 0.02) and PR- (P = 0.01) populations. This effect was not observed in the ER- BT474 cell line. These results suggest that in vivo tamoxifen decreases c-myc and c-erbB-2 RNA levels in breast cancer cells via two different mechanisms. To our knowledge this is the first evidence of in vivo down regulation of a gene by tamoxifen in ER- breast cancer cells.
Insights
Tamoxifen treatment significantly reduced c-myc and c-erbB-2 oncogene RNA levels in breast cancer patients. This study provides the first evidence of tamoxifen down-regulating genes in estrogen receptor-negative breast cancer cells in vivo.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast carcinomas often exhibit amplification and/or overexpression of oncogenes like c-myc, c-erbB-2, hst, and int-2.
- Tamoxifen is a widely used endocrine therapy for breast cancer, primarily targeting estrogen receptor-positive (ER+) tumors.
Purpose of the Study:
- To investigate the effect of tamoxifen on the RNA levels of key oncogenes (c-myc, c-erbB-2, hst, int-2) in human breast cancer patients.
- To explore potential differences in tamoxifen's effects based on estrogen receptor (ER) and progesterone receptor (PR) status.
Main Methods:
- In situ hybridization coupled with computer-aided quantification was used to measure oncogene RNA levels.
- RNA levels were compared between 19 breast cancer patients treated with tamoxifen for 3 weeks prior to surgery and 22 control patients.
- Correlation analyses were performed to assess relationships between gene amplification, expression, and receptor status.
Main Results:
- Tamoxifen treatment significantly decreased c-myc and c-erbB-2 RNA levels (P = 0.018, P = 0.003, respectively).
- hst and int-2 RNA levels were low and not significantly affected by tamoxifen.
- Gene amplification correlated with expression for c-erbB-2 and hst in controls.
- Tamoxifen diminished c-erbB-2 expression in ER- and PR-negative populations, an effect not seen in vitro.
Conclusions:
- Tamoxifen effectively down-regulates c-myc and c-erbB-2 RNA levels in vivo in breast cancer cells.
- Tamoxifen appears to act via distinct mechanisms in ER-positive and ER-negative breast cancers.
- This study presents novel evidence for tamoxifen's in vivo gene down-regulation in ER-negative breast cancer.