title: Non-genomic actions of estradiol and 4-OH-tamoxifen on murine breast cancer cells.
abstract: Estrogens and tamoxifen do not only exert their effects at the genomic level, but also play a role at the cell membrane activating downstream signaling pathways. We recently characterized an estrogen receptor-positive epithelial murine breast cancer cell line, LM05-E. Utilizing this cell line and MCF-7 cells, we compared the non-genomic effects of estradiol and 4-OH-tamoxifen. We showed that, similar to estradiol, tamoxifen activated the MAPK/ERK 1/2 pathway; however, we did not find activation of PI3K/AKT by either estradiol or tamoxifen. Short-term treatments with estradiol stimulated, whereas tamoxifen inhibited cell proliferation. Using pharmacological inhibitors we showed that the effect of estradiol was mediated by the MAPK/ERK 1/2 pathway, but that inhibition of this pathway did not affect tamoxifen. Surprisingly, however, blocking of PI3K/AKT signaling interfered with the inhibitory effect of tamoxifen. Analysis of the involvement of the EGFR support previous findings that designate this receptor as a mediator of the non-genomic effects of estradiol; blocking EGFR also reverses the inhibitory effect of tamoxifen. Finally, matrix metalloproteinases (MMPs) were confirmed to be involved in the proliferative effect of estradiol. These results demonstrated the novel non-genomic effects of tamoxifen and revealed that pathways downstream of EGFR and PI3K/AKT are involved in the inhibition of cell proliferation. Caution should be exercised when analyzing strategies that aim at combining endocrine therapy with specific signaling inhibitors.
authors.affiliation: Research Area, Institute of Oncology 'Ángel H. Roffo', Buenos Aires C1417DTB, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Raffo
authors.affiliation: Research Area, Institute of Oncology 'Ángel H. Roffo', Buenos Aires C1417DTB, Argentina.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Pontiggia
authors.affiliation: Research Area, Institute of Oncology 'Ángel H. Roffo', Buenos Aires C1417DTB, Argentina.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bal de Kier Joffé
authors.affiliation: Research Area, Institute of Oncology 'Ángel H. Roffo', Buenos Aires C1417DTB, Argentina.
authors.forename: Marina
authors.initials: M
authors.lastname: Simian
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D011799:Quinazolines; D020032:Tyrphostins; D013629:Tamoxifen; C101044:RTKI cpd; C016601:afimoxifene; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases