title: 17beta-estradiol promotes breast cancer cell proliferation-inducing stromal cell-derived factor-1-mediated epidermal growth factor receptor transactivation: reversal by gefitinib pretreatment.
abstract: The coordinated activity of estrogens and epidermal growth factor receptor (EGFR) family agonists represents the main determinant of breast cancer cell proliferation. Stromal cell-derived factor-1 (SDF-1) enhances extracellular signal-regulated kinases 1 and 2 (ERK1/2) activity via the transactivation of EGFR and 17beta-estradiol (E2) induces SDF-1 production to exert autocrine proliferative effects. On this basis, we evaluated whether the inhibition of the tyrosine kinase (TK) activity of EGFR may control different mitogenic stimuli in breast tumors using the EGFR-TK inhibitor gefitinib to antagonize the proliferation induced by E2 in T47D human breast cancer cells. EGF, E2, and SDF-1 induced a dose-dependent T47D cell proliferation, that being nonadditive suggested the activation of common intracellular pathways. Gefitinib treatment inhibited not only the EGF-dependent proliferation and ERK1/2 activation but also the effects of SDF-1 and E2, suggesting that these activities were mediated by EGFR transactivation. Indeed, both SDF-1 and E2 caused EGFR tyrosine phosphorylation. The molecular link between E2 and SDF-1 proliferative effects was identified because 1,1'-(1,4-phenylenebis(methylene))-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist, inhibited SDF-1- and E2-dependent proliferation and EGFR and ERK1/2 phosphorylation. EGFR transactivation was dependent on c-Src activation. E2 treatment caused a powerful SDF-1 release from T47D cells. Finally, in SKBR3, E2-resistant cells, EGFR was constitutively activated, and AMD3100 reduced EGFR phosphorylation and cell proliferation, whereas HER2-neu was transactivated by SDF-1 in SKBR3 but not in T47D cells. In conclusion, we show that activation of CXCR4 transduces proliferative signals from the E2 receptor to EGFR, whose inhibition is able to revert breast cancer cell proliferation induced by multiple receptor activation.
authors.affiliation: Sezione Farmacologia, Dipartimento Oncologia, Biologia e Genetica, Università di Genova, Viale Benedetto XV, 2, 16132 Genova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.forename: Carola
authors.initials: C
authors.lastname: Porcile
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lunardi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ratto
authors.forename: Roberto
authors.initials: R
authors.lastname: Favoni
authors.forename: Adriana
authors.initials: A
authors.lastname: Bajetto
authors.forename: Angelo
authors.initials: A
authors.lastname: Ferrari
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology*; D000077156:Gefitinib; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D054377:Chemokine CXCL12; D011799:Quinazolines; D004958:Estradiol; D066246:ErbB Receptors; D000077156:Gefitinib