Obesity is a known risk factor for estrogen-dependent postmenopausal breast cancer. Factors, including adipokines and inflammatory mediators (e.g. prostaglandin E2; PGE2), converge to increase aromatase expression, and hence estrogen production, within the adipose tissue of the breast, thereby increasing the risk of estrogen-dependent breast cancers.
We have previously shown that the metabolic pathway involving LKB1/AMPK, as well as the AMPK-regulated tumour suppressor p53, are inhibitory of aromatase expression, and that factors produced in obesity inhibit these pathways. We have recently demonstrated that p53 is a negative regulator of aromatase, that p53 expression and phosphorylation are inhibited by PGE2, and that there is a positive correlation between inactive p53 and aromatase in clinical samples of breast cancer. Conversely, we have showed that HIF1a is a potent stimulator of aromatase PII, and that it is stimulated by PGE2 and positively associated with aromatase expression in breast tumors. HIF1a is best characterized for its role in mediating responses to hypoxia and is negatively regulated by AMPK. These studies have also led us to explore whether other factors regulated in obesity may be involved in regulating aromatase in the breast. We have recently demonstrated that the gut hormone ghrelin, known to be inversely associated with obesity and a strong stimulator of AMPK, and its unacylted form, des-acyl ghrelin, are potent inhibitors of aromatase at picomolar concentrations. We also find that des-acyl ghrelin inhibits the estrogen-dependent growth of breast cancer cells in vitro and in vivo.
These findings therefore support a role for dysregulated metabolism as a driver of aromatase expression, and provide an additional molecular link between obesity and breast cancer in older women. The identification of these new molecular links has led to new therapeutic strategies, which we are currently exploring in preclinical and clinical studies.