Leptin attenuates the anti-estrogen effect of tamoxifen in breast cancer

BACKGROUND: Leptin is a circulating peptide hormone, encoded by the obesity (ob) gene, acting as a regulator of food intake via hypothalamic-mediated effects. Recent studies have shown that leptin and leptin receptor (ObR) are involved in the carcinogenesis and development of breast cancer. In addition, functional cross talk between leptin and estrogen signaling has been registered. Here, we investigated the relation of leptin and ObR expression with survival in women with breast cancer treated with the anti-estrogen tamoxifen, and whether leptin can interfere with the estrogen receptor alpha (ERα) and the effect of tamoxifen in breast cancer cells.

METHODS: The protein expression of leptin and ObR(b) in 114 breast cancer samples was evaluated by immunohistochemistry, quantified by Immunoreactivity Score (IRS) and correlated to survival and other clinicopathological features. The expression of ObR(b) in ERα positive MCF-7 breast cancer cells was examined by immunofluorescence and western blot. Leptin effect on cell proliferation was determined by MTT assay. The interference of leptin with tamoxifen on ERα degradation was studied by western blot and immunofluorescence. Effects of leptin on the transcriptional activity of ERα were explored using luciferase reporter assays.

RESULTS: Positive staining (Immunoreactivity Score, IRS≥1) of leptin and ObR isoform ObRb in breast cancer tissues were seen in 79.8% and 85.1% of patients respectively. In overall and in tamoxifen-treated breast cancer patients, leptin expression (IRS≥1) correlated with poor prognosis, (log-rank test, P=0.016, overall; P=0.031, tamoxifen-treated). Overexpressed ObRb was found by western blotting andimmunofluorescence in MCF-7 as well as in MDA-MB-231, T47D, and MDA-MB-435 cell lines. Tamoxifen (1000μM) significantly inhibited the proliferation of MCF-7 cells, degraded ERα and reduced ERα-dependent transcription from estrogen response element-containing promoter. On the contrary, simultaneous treatment with leptin (100ng/ml) significantly attenuated these effects, similar to the effects of estradiol.

CONCLUSIONS: Leptin correlated significantly with poor prognosis in overall and tamoxifen-treated breast cancer patients. Leptin interferes with the action of tamoxifen in MCF-7 cells, at least partly, through inducing increased nuclear expression of ERα. Thus, leptin may contribute to tamoxifen resistance and consequently, leptin suppression could be a novel way of circumventing resistance to anti-estrogen treatment.