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 ER alpha (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 ERa. Downregulation of ERa using small interfering RNA abolished leptin-induced STAT3 phosphorylation. Interestingly, leptin-mediated STAT3 activation was unaffected by co-stimulation with the ERa ligands estradiol (E2) or estrogen antagonists 10182,780 and tamoxifen, implying that enhancement of leptin-mediated STAT3 activity is independent of ERa ligands. We also detected ERa 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 ER alpha-dependent cell viability. Altogether, our results indicate that leptin-induced STAT3 activation acts as a key event in ER alpha-dependent development of malignant diseases.