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Plasma Membrane Estrogen Receptors Signal to Antiapoptosis in Breast Cancer

Department of Medicine The Long Beach Veterans Hospital Long Beach, California 90822

Chemotherapy or irradiation treatment induces breast cancer cell apoptosis, but this can be limited by estradiol (E₂) through unknown mechanisms. To investigate this, we subjected estrogen receptor-expressing human breast cancer cells (MCF-7 and ZR-75–1) to paclitaxel (taxol) or to UV irradiation. Marked increases in cell apoptosis were induced, but these were significantly reversed by incubation with E₂. Taxol or UV stimulated c-Jun N-terminal kinase (JNK) activity, which was inhibited by E₂. Expression of a dominant-negative Jnk-1 protein strongly prevented taxol- or UV-induced apoptosis, whereas E₂ inhibition of apoptosis was reversed by expression of constituitively active Jnk-1. As targets for participation in apoptosis, Bcl-2 and Bcl-xl were phosphorylated in response to JNK activation by taxol or UV; this was prevented by E₂. Taxol or UV activated caspase activity in a JNK-dependent fashion and caused the cleavage of procaspase-9 to caspase-9, each inhibited by E₂. Independently, the steroid also activated extracellular signal-regulated protein kinase activity, which contributed to the anti-apoptotic effects. We report novel and rapid mechanisms by which E₂ prevents chemotherapy or radiation-induced apoptosis of breast cancer, probably mediated through the plasma membrane estrogen receptor.

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