Eric Badia1,2, Marion Morena3,4, Céline Lauret3,4, Abdelhay Boulahtouf5,6,7, Nathalie Boulle8,9, Vincent Cavaillès5,6,7, Patrick Balaguer5,6,7, Jean Paul Cristol3. 1. PhyMedExp, UMR CNRS 9214, Inserm U1046, Université de Montpellier, 34295, Montpellier Cedex 5, France. eric.badia@univ-montp1.fr. 2. INSERM, U1046, IURC, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier, France. eric.badia@univ-montp1.fr. 3. PhyMedExp, UMR CNRS 9214, Inserm U1046, Université de Montpellier, 34295, Montpellier Cedex 5, France. 4. INSERM, U1046, IURC, 641 Avenue du Doyen Gaston Giraud, 34093, Montpellier, France. 5. IRCM, Institut de Recherche en Cancérologie de Montpellier, 34298, Montpellier, France. 6. INSERM, U1194, 34298, Montpellier, France. 7. ICM, Institut régional du Cancer de Montpellier, 34298, Montpellier, France. 8. CHU de Montpellier Arnaud de Villeneuve, 371, Avenue Doyen Gaston Giraud, 34295, Montpellier Cedex 5, France. 9. Université de Montpellier, 34090, Montpellier, France.
Abstract
BACKGROUND: Reactive oxygen species (ROS) are key players in the apoptotic effects induced by short-term tamoxifen treatment of breast cancer cells, but also in acquired resistance following long-term treatment. Whereas the use of the selective estrogen receptor down-regulator fulvestrant is promising, especially in patients who develop tamoxifen resistance, only few studies addressed its implication in the modulation of cellular redox status. METHODS: The regulation of (pro/anti)-oxidant players were first investigated at the mRNA level in a MCF-7-derived cell line after short-term (24 h) estradiol treatment. Long-term anti-estrogen treated MCF-7 derived cell lines were also developed: 3 months of 4-hydroxytamoxifen alone (MCF7L-OHTLT) or followed by 3 months of fulvestrant (MCF7L-ICILT). Growth properties, hormone sensitivity, receptor content, ROS production and relative mRNA expression of pro or antioxidant enzymes were evaluated in these long-term treated cell lines. RESULTS: Short-term estradiol treatment showed a hormone sensitivity of Nox2, GPx1, GPx2 and SOD1 mRNA levels. The long-term fulvestrant treatment (3 months) of MCF7L-OHTLT led to a reduced level of ROS production accompanied with a drastic drop of the accessory protein p22(phox) mRNA. This ROS reduction, although not clearly related to antioxidant enzymes level, seems to be involved in fulvestrant sensitivity of long-term anti-estrogen treated cells, as suggested by the effects of antiradical tempol treatment. CONCLUSION: When compared to long-term 4-hydroxytamoxifen-treated breast cancer cells, addition of fulvestrant treatment was able to diminish ROS production and p22(phox) mRNA level, and made cells more sensitive to growth inhibition induced by tempol. These effects may be a valuable asset of the fulvestrant treatment.
BACKGROUND:Reactive oxygen species (ROS) are key players in the apoptotic effects induced by short-term tamoxifen treatment of breast cancer cells, but also in acquired resistance following long-term treatment. Whereas the use of the selective estrogen receptor down-regulator fulvestrant is promising, especially in patients who develop tamoxifen resistance, only few studies addressed its implication in the modulation of cellular redox status. METHODS: The regulation of (pro/anti)-oxidant players were first investigated at the mRNA level in a MCF-7-derived cell line after short-term (24 h) estradiol treatment. Long-term anti-estrogen treated MCF-7 derived cell lines were also developed: 3 months of 4-hydroxytamoxifen alone (MCF7L-OHTLT) or followed by 3 months of fulvestrant (MCF7L-ICILT). Growth properties, hormone sensitivity, receptor content, ROS production and relative mRNA expression of pro or antioxidant enzymes were evaluated in these long-term treated cell lines. RESULTS: Short-term estradiol treatment showed a hormone sensitivity of Nox2, GPx1, GPx2 and SOD1 mRNA levels. The long-term fulvestrant treatment (3 months) of MCF7L-OHTLT led to a reduced level of ROS production accompanied with a drastic drop of the accessory protein p22(phox) mRNA. This ROS reduction, although not clearly related to antioxidant enzymes level, seems to be involved in fulvestrant sensitivity of long-term anti-estrogen treated cells, as suggested by the effects of antiradical tempol treatment. CONCLUSION: When compared to long-term 4-hydroxytamoxifen-treated breast cancer cells, addition of fulvestrant treatment was able to diminish ROS production and p22(phox) mRNA level, and made cells more sensitive to growth inhibition induced by tempol. These effects may be a valuable asset of the fulvestrant treatment.