Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells.
Adipositas correlates with an enhanced risk of developing malignant diseases such as breast cancer, endometrial tumor or prostate carcinoma, but the molecular basis for this is not well understood. Potential mechanisms include increased bioavailability of adipocytokines (e.g. leptin) and steroid hormones. Here, we investigated cross-talk between ERalpha (estrogen receptor alpha) and leptin-induced activation of signal transducer and activator of transcription 3 (STAT3), a transactivator of important oncogenes. Upon leptin binding to its receptor Ob-RL (obesity receptor), STAT3 tyrosine phosphorylation and transactivation activity were enhanced by simultaneously expressing ERalpha. Downregulation of ERalpha using small interfering RNA abolished leptin-induced STAT3 phosphorylation. Interestingly, leptin-mediated STAT3 activation was unaffected by co-stimulation with the ERalpha ligands estradiol (E2) or estrogen antagonists ICI182,780 and tamoxifen, implying that enhancement of leptin-mediated STAT3 activity is independent of ERalpha ligands. We also detected ERalpha binding to STAT3 and JAK2 (Janus kinase 2), resulting in enhanced JAK2 activity upstream of STAT3 in response to leptin that might lead to an increased ERalpha-dependent cell viability. Altogether, our results indicate that leptin-induced STAT3 activation acts as a key event in ERalpha-dependent development of malignant diseases.
Binai
Nadine A
NA
Junior Research Group, Paul-Ehrlich-Institute, Langen, Germany.
Damert
Annette
A
Carra
Gert
G
Steckelbroeck
Stephan
S
Löwer
Johannes
J
Löwer
Roswitha
R
Wessler
Silja
S
D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D017931:DNA Primers; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D020738:Leptin / Q000502:physiology*; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014162:Transfection
D017931:DNA Primers; D047628:Estrogen Receptor alpha; D020738:Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human