Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if
leptin-induced
aromatase enhances
estrogen production and induces
tumor cell growth stimulation. To this end,
breast cancer cells were incubated with
leptin in the absence or presence of inhibitor pretreatment, and changes in
aromatase and
cyclooxygenase-2 (COX-2) expression were evaluated at the
mRNA and
protein levels. Transient transfection assays were performed to examine the
aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine
protein expression.
Leptin induced
aromatase expression,
estradiol production, and promoter activity in
breast cancer cells.
Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by
leptin.
Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition,
leptin induced COX-2 expression, promoter activity, and increased the production of
prostaglandin E2. Finally, a
COX-2 inhibitor and
aromatase inhibitor suppressed
leptin-induced cell proliferation in MCF-7
breast cancer cells. Together, our data show that
leptin increased
aromatase expression in
breast cancer cells, which was correlated with COX-2 upregulation, mediated through CRE activation and cooperation among multiple signaling pathways.