Estrogens and PTP1B function in a novel pathway to regulate aromatase enzymatic activity in breast cancer cells

Local estrogen production by aromatase is an important mechanism of autocrine stimulation inhormone-dependent breast cancer. We have previously shown that 17-beta estradiol (E2) rapidlyenhances aromatase enzymatic activity through an increase of tyrosine protein phosphorylationcontrolled by the activity of the c-Src kinase in breast cancer cells. Here,weinvestigated the tyrosinephosphatase PTP1B as a potential regulator of aromatase activity. We demonstrated a specificassociation between PTP1B and aromatase at protein-protein level and a reduction of aromataseactivity in basal and E2-treated MCF-7 and ZR75 breast cancer cells when PTP1B was overexpressed.Indeed, a specific tyrosine phosphatase inhibitor increased basal and E2-induced enzymatic activityas well as tyrosine phosphorylation status of the purified aromatase protein. Moreover, E2 throughphosphatidylinositol 3 kinase/serine-threonine kinase activation caused a significant decrease ofPTP1B catalytic activity along with an increase in its serine phosphorylation. Concomitantly, thephosphatidylinositol 3 kinase inhibitor LY294002 or a dominant negative of serine-threonine kinasewas able to reduce the E2 stimulatory effects on activity and tyrosine phosphorylation levelsof aromatase. Taken together, our results suggest that E2 can impair PTP1B ability to dephosphorylatearomatase, and thus it increases its enzymatic activity, creating a positive feedback mechanismfor estradiol signaling in breast cancer.