The initial hypothesis that metabolic pathways regulate the expression of the estrogen biosynthetic enzyme aromatase in the adipose developed from the observation that boys with Peutz Jeghers Syndrome develop gynecomastia or breast tissue, with mutations in the AMPK upstream kinase, LKB1, being the major cause of the syndrome. We also found that LKB1 and AMPK are tightly regulated by factors known to be altered in obesity, including inflammatory mediator PGE2 and the adipokines, leptin and adiponectin. This work therefore provided one of the first molecular links between obesity and breast cancer in older women and led to the hypothesis that activating AMPK will lead to the breast-specific inhibition of aromatase. The role of AMPK-interrelated metabolic pathways in regulating aromatase in the breast was also then further explored. We were firstly interested in HIF1a, a mediator of hypoxic responses in cancer that drives vascularization of tumors and aerobic glycolysis to sustain tumor growth, as it has been shown to be negatively regulated by AMPK via effects on mTOR. We discovered that HIF1a stimulates aromatase and estrogen production in breast fat, and that PGE2 drives this process independent of oxygen tension. Contrary to HIF1a, the tumor suppressor p53 inhibits aerobic glycolysis and is stimulated by AMPK in times of low nutrient availability. We demonstrated that p53 inhibits aromatase expression and that it is, in turn, inhibited by PGE2. This work was further supported by findings in patients with Li-Fraumeni Syndrome, a hereditary cancer syndrome that often occurs in patients with germline mutations in the TP53 gene, that encodes the tumor suppressor p53. These patients tend to develop hormone receptor-positive breast cancer and we discovered that aromatase is elevated in the breast adipose tissue of these patients. The broader implications of this work are that inflammatory factors and adipokines that are increased in obesity alter the metabolism of the breast stroma, leading to a microenvironment that is conducive to breast cancer development. We are currently exploring these relationships in other hereditary cancer syndromes and using this information to identify new therapeutic strategies to break the linkage between obesity and breast cancer.
