Obesity and breast cancer risk is a Research Project for the Research Group, under the Obesity and breast cancer risk.
Obesity is a known risk factor for postmenopausal breast cancer, due to the direct and indirect impact of factors produced by adipose tissue are on tumour growth. It is increasingly clear that both obesity and cancer are 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 adipose tissue and tumour cells produce inflammatory cytokines and prostaglandins. 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.
Increased aromatase expression of adipose relating to obesity and cancer is a consequence of activation of a specific promoter, PII. The promoter-specific regulation of aromatase is of great significance, as promoter PII does not drive aromatase expression in any other tissues in postmenopausal women. Our group has made major contributions to the understanding of the role of metabolic pathways in regulating aromatase in the adipose in response to obesity-associated inflammatory factor prostaglandin E2 (PGE2) and adipokines.
We have demonstrated that the expression and activity of a key protein involved in metabolism, LKB1 is regulated by several factors, including sex hormones. The hypothesis that LKB1 may be involved in reciprocally regulating aromatase in the breast came from the observation that boys with Peutz Jeghers Syndrome (PJS) have symptoms of oestrogen excess, including gynaecomastia and advanced bone age. Our group has recently characterised the relationship between LKB1 and aromatase in testicular Sertoli cells and breast epithelial cells of two boys with PJS.
Our investigations in two unrelated cases of different ages and with different mutations demonstrates that heterozygous mutations in the STK11 gene can lead to the decreased stability of mutated LKB1 proteins. However, loss of expression and activity of the second allele is necessary for the increased expression of aromatase. The broader implication is that LKB1 may be central to the regulation of oestrogen biosynthesis in a number of tissues and physiological and pathophysiological situations.
Further evidence to support the relationship between LKB1 signalling and aromatase is that LKB1 inhibits gluconeogenesis in the liver by stimulating AMPK phosphorylation and inhibiting nuclear entry of the CREB coactivator CRTC2. We have since shown that CRTC proteins are potent and necessary activators of aromatase PII in human breast adipose stromal cells, and that the upstream kinases LKB1/AMPK are inhibitory. Moreover, factors increased in obesity such as leptin and PGE2 inhibit LKB1/AMPK, thereby providing a molecular link between obesity and breast cancer.
Aromatase regulation by LKB1/AMPK interrelated pathways
AMPK regulates factors p53 and HIF1a, with P53 mutations shown to occur in >50% of breast tumours. Recent evidence, however, confirms these mutations are rare in the breast stroma. Our NHMRC-funded work has demonstrated that p53 is a negative regulator of aromatase and confirmed PGE2 as an effective inhibitor of p53 expression and phosphorylation. There is a positive correlation between inactive p53 and aromatase in clinical samples of breast cancer. Conversely, our group has shown that potent aromatase PII stimulator HIF1a, is positively associated with aromatase expression in breast tumour when stimulated by PGE2, These findings sparked interest in identifying new modulators of aromatase and we are currently exploring the role of other important metabolic pathways for their effect on aromatase expression in the breast.
MIMR-PHI collaborator Professor Evan Simpson
University of Melbourne collaborator Professor Stephen Fox
Tohoku University collaborator Prof Hironobu Sasano
University of Western Australia collaborator Prof Catherine Choong