Obesity is a known risk factor for postmenopausal breast cancer - factors produced by adipose tissue are known to directly and indirectly affect tumour growth. It is increasingly clear that both obesity and cancer arise as a consequence of dysregulated metabolism, both in response to altered energy status and endocrine factors, and to intrinsic changes within cells. Moreover, both obesity and cancer lead to localised inflammation, whereby inflammatory cytokines and prostaglandins are produced by adipose tissue and tumour cells. Interestingly, these factors converge to increase aromatase expression, and hence oestrogen production, within the adipose tissue of the breast, thereby increasing the risk of oestrogen-dependent breast cancer.
AMPK, considered a master regulator of energy homeostasis, and its upstream kinase LKB1, are negative regulators of aromatase expression in adipose stromal cells by causing cytoplasmic sequestration of the CREB-coactivator CRTC2. Obesity-associated inflammatory factor PGE2 and leptin inhibit LKB1/AMPK, causing CRTC2 to enter the nucleus, bind to the proximal promoter PII of aromatase and increase its expression. Following on from this work, we have identified additional metabolic pathways as potent regulators of aromatase. On the one hand, p53, known for its tumour suppressor activity and now accepted to play an important role in maintaining energy homeostasis, acts as a transcriptional repressor of aromatase in adipose stromal cells and is downregulated by PGE2. Conversely, HIF1, which has an established role in the vascularisation of tumours and is emerging as a key mediator of metabolic responses in cancer, is stabilised by PGE2 in adipose stromal cells under normoxic conditions and is a potent stimulator of aromatase expression. 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, is a potent inhibitor of aromatase at picomolar concentrations. These studies have also led us to discover that activation of AMPK, including with the commonly prescribed anti-diabetic drug metformin, can inhibit aromatase in an adipose-specific manner, suggesting that detrimental effects associated with current endocrine therapies would be avoided using this therapeutic strategy.
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. Current studies are aimed at examining whether drugs which target these pathways have potential for the treatment of oestrogen-dependent cancers.