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Antiestrogens are pro‐apoptotic in normal human breast epithelial cells

Estrogens promote cell proliferation in normal and transformed mammary epithelial cells by inducing expression of hormone‐responsive genes involved in the cell cycle. The action of antiestrogens is therefore central in regard to their potent inhibitory effects on estrogen‐induced cell growth. We used normal human epithelial breast cells from primary cultures (HBE cells) to study hormonal (estrogen and antiestrogen) regulation on 3 key proteins involved in the apoptotic process: Bcl‐2, p53 and caspase‐3. The mammary adenocarcinoma cell line, MCF‐7, was also used to study the molecular regulation of Bcl‐2. In both HBE and MCF‐7 cells, we found that estradiol (E2) induced an increase in Bcl‐2 mRNA levels. This effect was counteracted in the presence of a pure antiestrogen, ICI 182780 (ICI). Alone, ICI did not modify either the Bcl‐2 protein or mRNA levels in HBE cells, whereas in MCF‐7, a strong downregulation of Bcl‐2 mRNA was observed. In parallel, in HBE cells, we observed that E2 caused a decrease in p53 and caspase‐3 protein levels, whereas ICI alone increased p53 and caspase‐3 protein levels. The ICI effects on p53 and caspase‐3 were partially counteracted by E2. Under the same experimental conditions, ICI exerts a potent pro‐apoptotic effect, which was not counteracted by E2. In contrast, 4‐hydroxytamoxifen was slightly weaker as a pro‐apoptotic agent in HBE cells and its effects were reversed by E2. We demonstrate that in HBE cells, ICI reverses the anti‐apoptotic action of E2 and alone acts as a highly potent pro‐apoptotic molecule. These results provide new insight into treatment for breast cancer prevention. © 2003 Wiley‐Liss, Inc.