The risk of postmenopausal breast cancer increases two-fold in obesity, and the majority of postmenopausal and obesity-related breast cancers are oestrogen-dependent. The adipose tissue is the major source of oestrogens in postmenopausal women and oestrogen production within breast adipose stromal cells (ASCs) drives tumour growth. Our laboratory's work has focused on understanding how dysregulated metabolism, as is seen in obesity and cancer, increases oestrogen production within the breast. In this regard, we have studied a number of metabolic pathways, including those which modulate the activity of CRTC2 and HIF1α, for their role in regulating a key regulator of oestrogen biosynthesis, aromatase.
AMPK is a master regulator of energy homeostasis and is activated by upstream kinase LKB1. Our work has demonstrated that LKB1/AMPK are negative regulators of aromatase expression in ASCs by sequestering the CREB-coactivator CRTC2 in the cytoplasm. Inflammatory factor PGE2 (produced in obesity and by tumour cells) and the adipokine leptin inhibit LKB1/AMPK. As a result, CRTC2 enters the nucleus, binds to the proximal promoter PII of aromatase via cAMP response elements (CRE) and increases its expression. Conversely, adiponectin, produced by lean adipose tissue, stimulates LKB1/AMPK and inhibits the PGE2-mediated expression of aromatase. We have recently identified a putative hypoxia response element which overlaps the proximal CRE of aromatase PII. HIF1α has an established role in the vascularisation of tumours and is emerging as a key mediator of metabolic responses in cancer. We now demonstrate that HIF1α binds directly to aromatase promoter PII and acts cooperatively with CREB to stimulate aromatase expression. HIF1α is increased in tumour-associated ASCs a phenomenon mediated, at least in part, by PGE2.
Taken together, our work suggests that dysregulated metabolism is not only a characteristic of adipocytes or the tumourous epithelium, but also of the breast adipose stroma, and that aromatase expression is tightly regulated by these metabolic pathways in obesity and breast cancer. As a result, these studies have led to the exploration of therapeutics which target metabolic pathways for their use in the treatment of obesity-related postmenopausal breast cancer.