A new role of leptin as amplifier of estrogen signaling in breast cancer.

Background of Study: Leptin produced predominantly by adipose tissue, is able to stimu¬late normal and tumor cell growth. We demonstrated that leptin up-regulates aromatase gene expression in MCF-7 cells evidencing its important role in situ estradiol production and estrogen-dependent breast cancer progression. Estrogen receptor (ERa) that plays an essential role in breast cancer development. can be transcriptionally activated in Iigand ¬independent manner through MAPK signal. Objectives: Sine leptin is able to activate the MAPK pathway. We investigated the ability of leptin lo transactivate ERa. Methods: In MCF-7 cells we examined through immunocytochemical staining, RT-PCR and Western Blotting the expression of ERa upon leptin treatment. Functional studies, in MCF-7 and HeLa cells, with a ERE reporter gene and ERa wild type or different deleted ERa constructs were performed under E2. TAM and/or leptin treatments. Results: Leptin was able to reproduce the classical features of ERa transactivation: a nuclear localization and a down-regulation of its mRNA and protein levels. Transfection stud¬ies revealed that N-terminal transcriptional activation functional appears essential for ERa response to leptin. As result of the distinct action of E2 and leptin on the two functional domains respectively the combined exposure to the two hormones produced a synergistic effect on the activation of ERa and reduced the action of some antiestrogens tested in the same circumstances. Conclusions: We demonstrated a new role of leptin as amplifier of estradiol signal through a direct activation of ERa. Besides, high leptin levels, facilitating the functional activation of ERa, may work on a progressive loss of estrogen-dependence of ER+ cells.