Role of ghrelin and novel ghrelin receptors in aromatase regulation and breast cancer cell growth in obesity related postmenopausal breast cancer (#43)
Background: The majority of postmenopausal breast cancers are dependent on oestrogens produced from breast adipose stromal cells (ASCs) as a consequence of the increased expression of aromatase.Ghrelin, an orexigenic peptide, and its precursor des-acyl ghrelin (DAG), have recently been shown to play a role in breast cancer. Ghrelin acts through GHSR1a but DAG does not, and it is believed that ghrelin receptor-like receptors (GRLRs) exist. In this study it was hypothesized that ghrelin inhibits breast cancer cell growth and aromatase expression in ASCs. The aims of this study were to determine 1) the effect of ghrelin on aromatase in ASCs, 2) the effect of ghrelin in regulating breast cancer cell proliferation and 3) the relative roles of GHSR1a and GRLRs in mediating the effects of ghrelin in ASCs and breast cancer cells. Methods: Primary human ASCs were isolated from reduction mammoplasty. Real-time PCR was used to determine the effect of ghrelin and DAG on aromatase transcript expression. Aromatase activity assays were used to determine the effects of ghrelin and capromorelin (GHSR1a selective agonist) on aromatase activity. High content screening was used to determine the effect of ghrelin on MCF-7 breast cancer cell growth. Results: Ghrelin and DAG inhibited aromatase transcript expression in ASCs at concentrations of 10, 100 and 1000 pM for ghrelin (P≤0.05) and concentrations of 100 and 1000pM for DAG (P≤0.05). Ghrelin also decreased the oestrogen-mediated proliferation of MCF-7 cells (P≤0.05). Ghrelin but not capromorelin inhibited aromatase activity at concentration of 1nM (P≤0.05) and GHSR1a was not detected in ASCs using Western blot, further supporting the existence of GRLRs. Conclusions: Ghrelin inhibits breast cancer cell growth via direct and indirect mechanisms that appear to be mediated via GRLRs. Further studies will determine whether we can target these receptors to treat breast cancer.