Received for publication July 19, 2007.
Revised October 4, 2007.
Accepted for publication October 23, 2007.

17-ESTRADIOL PROMOTES BREAST CANCER CELL PROLIFERATION INDUCING SDF-1-MEDIATED EGFR TRANSACTIVATION: REVERSAL BY GEFITINIB PRE-TREATMENT

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 ERK1/2 activity via the transactivation of EGFR and 17-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 non additive 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 since 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, while HER2 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.

Key words: Chemotactic peptides, NGF/EGF, Sex hormones, Src and other nonreceptor tyrosine kinases, MAP Kinase, Mechanisms of cell killing/apoptosis

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