title: Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer.
abstract: 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 antiapoptotic 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.
authors.affiliation: Department of Medicine, The Long Beach Veterans Hospital, California 90822, USA.
authors.forename: M
authors.initials: M
authors.lastname: Razandi
authors.forename: A
authors.initials: A
authors.lastname: Pedram
authors.forename: E R
authors.initials: ER
authors.lastname: Levin
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001943:Breast Neoplasms; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D004792:Enzyme Precursors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000528:radiation effects; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D004792:Enzyme Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D051020:bcl-X Protein; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D017239:Paclitaxel