In situ estrogen production by aromatase conversion from androgens plays an important role in breast tumor promotion. Here, we show that 17- 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 non-receptor tyrosine-kinase c-Src in E₂-stimulated aromatase activity since inhibition of its signalling 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 crosstalk 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 non genomic autocrine loop between E₂ and aromatase in breast cancer cells.