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Rapid Estradiol/ER Signaling Enhances Aromatase Enzymatic Activity in Breast Cancer Cells

Departments of Pharmaco-Biology (S.C., I.B., C.G., H.Q., G.G., R.M., D.B.) and Cell Biology (P.R., S.A.) and Centro Sanitario (C.G., S.A.), University of Calabria, 87030 Arcavacata di Rende (Cosenza), Italy

Address all correspondence and requests for reprints to: Professor Sebastiano Andò, Department of Cell Biology University of Calabria, Arcavacata di Rende (CS) 87030, Italy. E-mail: sebastiano.ando{at}unical.it.

In situ estrogen production by aromatase conversion from androgens plays an important role in breast tumor promotion. Here, we show that 17β-estradiol (E₂) can rapidly enhance aromatase enzymatic activity through an increase of aromatase protein phosphorylation in breast cancer cell lines. In vivo labeling experiments and site-directed mutagenesis studies demonstrated that phosphorylation of the 361-tyrosine residue is crucial in the up-regulation of aromatase activity under E₂ exposure. Our results demonstrated a direct involvement of nonreceptor tyrosine-kinase c-Src in E₂-stimulated aromatase activity because inhibition of its signaling abrogated the up-regulatory effects induced by E₂ on aromatase activity as well as phosphorylation of aromatase protein. In addition, from our data it emerges that aromatase is a target of cross talk between growth factor receptors and estrogen receptor signaling. These findings show, for the first time, that tyrosine phosphorylation processes play a key role in the rapid changes induced by E₂ in aromatase enzymatic activity, revealing the existence of a short nongenomic autocrine loop between E₂ and aromatase in breast cancer cells.

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Ligands:   Tamoxifen  |  17β-estradiol  |  Fulvestrant