Background: The majority of breast cancers are oestrogen receptor positive (ER+). The aromatase enzyme catalyses the conversion of androgens into oestrogens and its expression in breast adipose is a major driver of oestrogen-dependent breast cancer after menopause. Aromatase inhibitors are currently first-line therapy for ER+ breast cancer, but their use is also associated with side-effects due to inhibition of aromatase in bone. Our lab has discovered that the gut-derived peptide hormone des-acyl ghrelin (DAG) inhibits the growth of ER+ breast cancer cells as well as aromatase activity.
Aims and hypotheses: We hypothesise that DAG may be efficacious for the treatment of ER+ breast cancer. We aim to examine the effect of DAG on aromatase activity and breast tumour growth in vitro and in vivo.
Methods: Effect of DAG on the oestrogen-dependent proliferation of breast cancer cell lines (MCF7, ZR75) was examined by quantifying EdU incorporation in vitro and in vivo. In vitro studies were performed using 3D cultures, whereas the effect of DAG in vivo was examined in mammary fat pad-xenografted balb/c nude mice. The effect of DAG on aromatase activity was examined in breast cancer explants using the tritiated water-release assay.
Results: DAG (10pM, 100pM and 1000pM) significantly inhibits the oestrogen-stimulated number and proliferation of MCF7 and ZR75 cells in vitro (n=3; P≤ 0.05). Consistently, DAG (10ug/kg and 100ug/kg) also significantly inhibits MCF7 and ZR75 (n=3/group; P≤ 0.0001) tumour growth in the presence of oestradiol in vivo compared to vehicle control. Moreover, DAG inhibits aromatase activity at 10pM and 100pM (P ≤ 0.005) in breast cancer tissue explants.
Conclusions: Our findings suggest that DAG will inhibit breast cancer growth via direct effects on cell proliferation and indirect effects on oestrogen production. Therefore, DAG or DAG mimetics may be useful as possible ER+ breast cancer therapeutics in the future.