Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells

Abstract

Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis of estrogen responsive human breast cancer MCF-7 cells. Transfer of MCF-7 cells to a culture-medium without estrogens reduced their intracellular p26Bcl-2 levels by 50%. Inclusion of 0.1 microM estradiol in the medium produced approximately a four-fold increase in p26Bcl-2, but not p29Bcl-x1, or p21Bax levels; the expression of the c-myc and mdr-1 genes remained unchanged. Estradiol-induced four-fold increase in the ratio of the p26Bcl-2 to p21Bax levels caused a significant decline in the lethal, kilobase size DNA fragments of apoptosis, which had resulted when MCF-7 cells were cultured in a medium without estrogen. In addition, in MCF-7 cells, estradiol-induced increase in the intracellular p26Bcl-2 to p21Bax ratios was associated with a significant reduction in the large-sized DNA fragmentation induced by treatment with taxol. The increased ratios also protected MCF-7 cells against taxol-mediated cytotoxicity as assessed by the MTT assay. These results suggest that by modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.

Inhibition of in vitro angiogenesis by 2‐methoxy‐ and 2‐ethyl‐estrogen sulfamates

“…29,30 Phosphorylation of BCL-2 interferes with its dimerization with the proapoptotic protein BAX and can thus induce cells to undergo apoptosis. 31 Evidence was obtained in the present study that 2-MeOEMATE could induce BCL-2 phosphorylation in HUVECs as previously found to occur in MCF-7 cells. 16 Changes in HUVEC morphology and the assessment of free nucleosome levels in drug-treated cells confirmed that these cells were undergoing apoptosis.…”

Serine protease inhibitor TPCK prevents Taxol-induced cell death and blocks c-Raf-1 and Bcl-2 phosphorylation in human breast carcinoma cells

“…In agreement with previous ®ndings (Huang et al, 1997b;Saunders et al, 1997), Taxol-induced apoptosis in MCF-7 cells. Morphological analysis of Taxoltreated cells revealed cardinal features of apoptosis including chromatin condensation and nuclear fragmentation (Figure 1).…”

High level expression of differentially localized BAG-1 isoforms in some oestrogen receptor-positive human breast cancers

“…We first analysed cells grown in normal conditions (phenol red containing medium and complete FCS) and cells additionally exposed for 2 or 4 days to the pure anti-oestrogen ICI 182 780 (Wakeling et al, 1991). Consistent with previous reports (Texeira et al, 1995;Huang et al, 1997), exposure of MCF7 cells to ICI 182 780 significantly down-regulated BCL-2 expression ( Figure 5). By contrast, BAG-1 expression was not altered.…”

“…Indeed, BCL-2 is regulated by oestrogens in breast cancer cells (Texeira et al, 1995;Huang et al, 1997) and BAG-1 and BCL-2 are co-regulated in some systems (Adachi et al, 1996). We therefore examined effects of modulating oestrogen signalling on BAG-1 and BCL-2 expression in oestrogen-responsive MCF7 cells.…”

“…Thus, apoptosis and oestrogen-responsive are closely linked pathways in breast cancer. One pathway by which oestrogens may promote viability of breast cancer cells is via induction of BCL-2 since BCL-2 expression in MCF7 breast cancer cells is regulated by oestrogens and enforced BCL-2 expression suppresses MCF7 cell apoptosis (Texeira et al, 1995;Huang et al, 1997). This may explain the frequent co-expression of ER and BCL-2 in breast tumours (Bharagava et al, 1994;Leek et al, 1994;Silvestrini et al, 1994).…”