After the menopausal transition, the ovaries cease to make oestrogens, yet the incidence of breast cancer increases with aging and the majority of these tumours are ER positive. So, where is the oestrogen driving this tumour development coming from? Several extra-gonadal sites synthesize oestrogens from circulating C19 steroids, such as bone, brain, and adipose. The largest of these depots is the adipose tissue, and increased BMI is associated with increased breast cancer risk, so, given the global pandemic of obesity, we are faced with the daunting prospect that tens of millions more women may be at risk of breast cancer in their later years than was previously thought. Yet the mechanisms linking obesity to cancer risk are not completely understood. Factors increased in obesity such as leptin and insulin appear to increase breast cancer risk, probably via activation of the Akt/mTOR/HIF1α/SREBP pathways, whereas adiponectin has been shown to decrease the risk in a number of studies. This appears to be due, in part, to activation of the LKB1/AMPK pathway. The anti-diabetic drug metformin has also been shown to decrease the risk of breast cancer, and it also acts to stimulate AMPK.
Given the capacity of adipose tissue to express aromatase, the enzyme responsible for oestrogen biosynthesis, we looked for a link between obesity and increased aromatase expression in breast adipose. In the presence of a tumour, aromatase expression locally in the breast is stimulated by inflammatory mediators produced by the tumour such as PGE2 and TNFα. We observed that AMPK is a potent inhibitor of aromatase expression stimulated by PGE2 in breast adipose stromal cells. The mechanism involves sequestration in the cytoplasm by phosphorylation of a CREB coactivator, CRTC2. The LKB1/AMPK pathway is inhibited in breast stromal cells by leptin and by PGE2, and is stimulated by adiponectin. Since leptin is increased, and adiponectin is decreased, in obesity, this provides a new mechanism whereby obesity increases breast cancer risk. Moreover, we observed that metformin also inhibits aromatase expression in breast stromal cells, associated with an increase in LKB1/AMPK activity. A number of trials are currently underway to establish if metformin could find utility as a breast cancer therapeutic agent, and we have commenced a study to establish if metformin treatment in the neoadjuvant and adjuvant settings results in an increase in the activity of the LKB1/AMPK pathway and a decrease in the expression of aromatase in the female breast.
An advantage of metformin as an inhibitor of aromatase expression is that such inhibition is breast-specific in the post-menopausal woman. This is due to the unique use of tissue-specific promoters by the aromatase gene to regulate its tissue-specific expression. Currently phase III aromatase inhibitors are used as hormonal therapy for breast cancer, but their use has significant side-effects including bone loss hot flushes and arthralgia, due to global inhibition of aromatase catalytic activity. Use of AMPK activators such as metformin should inhibit aromatase expression uniquely in the breast, but leave protected other sites of expression such as bone and brain, where oestrogens have important functions.