Poster Presentation 27th Lorne Cancer Conference 2015

Targeting Oestrogen-Dependent Breast Cancer: Ghrelin Receptor Agonists As Novel Therapeutics (#115)

CheukMan Cherie Au 1 , Maria Docanto 1 , Brid Callaghan 2 , John Furness 2 , Kristy Brown 1 3
  1. Metabolism & Cancer Laboratory, Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia
  2. Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria , Australia
  3. Department of Physiology, Monash University, Clayton, Victoria , Australia

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 ghrelin inhibits aromatase and the growth of ER+ breast cancer cells.

Aims and hypotheses: We hypothesised that ghrelin receptor agonists may be useful for the treatment of ER+ breast cancer. We aim to examine the effect of ghrelin receptor agonists on adipose and bone aromatase as well as evaluate their effect on breast tumour growth in vitro.

Methods: The effect of ghrelin receptor agonists (ghrelin, des-acyl ghrelin (DAG); AZP531 and capromorelin) was examined in primary human adipose stromal cells (ASCs) and osteoblasts (bone cells), as well as normal (MCF10A) and cancer (MCF7) human breast epithelial cell lines. Aromatase transcript expression and activity was assessed using QPCR and tritiated water-release assays, respectively. Effects on breast epithelial cell number and proliferation were assessed using high content screening and Click It EdU assay.

Results: Our results demonstrate that ghrelin and DAG (0-1000pM) inhibit aromatase transcript expression and activity in human ASCs. AZP531 and capromorelin had no effect. Ghrelin did not inhibit aromatase in osteoblasts. Moreover, ghrelin, DAG and AZP531, but not capromorelin, inhibited the oestrogen-stimulated proliferation of MCF7 cells. Conversely, DAG and AZP531 had no effect on MCF10A cell growth.

Conclusions: Our findings suggest that ghrelin receptor agonists will inhibit breast cancer cell proliferation without affecting the bone. Ghrelin mimetics may be useful as possible ER+ breast cancer therapeutics in the future.