Rapid estradiol/ERalpha signaling enhances aromatase enzymatic activity in breast cancer cells.
In situ estrogen production by aromatase conversion from androgens plays an important role in breast tumor promotion. Here, we show that 17beta-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 alpha 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.
Catalano
Stefania
S
Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende (CS) 87030, Italy.
Barone
Ines
I
Giordano
Cinzia
C
Rizza
Pietro
P
Qi
Hongyan
H
Gu
Guowei
G
Malivindi
Rocco
R
Bonofiglio
Daniela
D
Andò
Sebastiano
S
D000595:Amino Acid Sequence; D001141:Aromatase / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D046912:Multiprotein Complexes; D017978:Receptors, Growth Factor; D019000:Phosphotyrosine; D004958:Estradiol; D001141:Aromatase; D066246:ErbB Receptors; D019061:src-Family Kinases