Obesity and breast cancer risk

Summary

We have provided detailed evidence to suggest that the association of obesity with increased breast cancer risk is mediated via the adipokines leptin and adiponectin through the LKB-1/AMP kinase pathway.

Description

We have shown the LKB-1/AMP kinase pathway is inhibitory of aromatase expression within the breast. In breast adipose stromal cells this pathway inhibits aromatase expression by sequestration of CRTC2 in the cytoplasm. CRTC2 is a coactivator of CREB, which is required for breast-specific regulation of aromatase.

We have also found that leptin, whose levels are increased in obesity, inhibits this pathway and thus increases aromatase expression. By contrast adiponectin whose levels are decreased in obesity stimulates the LKB-1/AMPK pathway and thus leads to inhibition of aromatase expression.

Our current work is focused on understanding the details of this regulation.

Since in the postmenopausal woman local aromatase expression in the breast is the main source of oestrogen driving breast cancer development, this provides a powerful mechanism to explain in part the role of obesity in breast cancer risk.

Outcomes

The mechanism outlined above offers new therapeutic opportunities for breast cancer prevention, namely the use of AMPK inhibitors. One of these, Metformin, has been in use for years to treat insulin resistance and type II diabetes.
Trials are currently under way to determine its efficacy as a breast cancer therapeutic agent. However, its mechanism of action to stimulate AMPK activity is poorly understood. Thus there is a need to develop new inhibitors with higher specificity and affinity.

Funding

National Health and Medical Research Council
Victorian Breast Cancer Consortium
Terry Fox Foundation (Fellowship)
Department of Defense, USA (Breast Cancer Research Program)

Selected Publications

Brown KA, McInnes KJ, Hunger NI, Oakhill JS, Steinberg GR, Simpson ER. The subcellular localisation of CRTC2 provides a link between obesity and breast cancer in postmenopausal women. Cancer Res 69: 5392-5399 (2009)

Mahendroo MS, CR Mendelson and ER Simpson: Tissue-specific and hormonally-controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J Biol Chem 268:19463-19470 (1993).

Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER. Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337(2)91-95 1997.

Jones MEE, AW Thorburn, KL Britt, KN Hewitt, NG Wreford, J Proietto, OK Oz, BJ Leury, KM Robertson, S Yao ER Simpson. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. PNAS 97:12735-12740, 2000

Clyne CD, Speed CJ, Zhou J, Simpson ER. Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. J Biol Chem 277:20591-20597, 2002

Safi R, Kovacic A, Gaillard S, Murata Y, Simpson ER, McDonnell DP, Clyne CD. Coactivation of liver receptor homologue-1 by peroxisome proliferators-activated receptor gamma coactivator-1 alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy. Cancer Res 65(24):11762-11770 2005

McInnes KJ, Corbould A, Simpson ER, Jones ME. Regulation of AMPK and lipogenesis by androgens contributes to visceral obesity in an estrogen deficient state. Endocrinology 147: 5907-5913 (2006)

PHI Research Team