Effect of Stromal Adipokines on Breast Cancer Development

Obesity increases the risk of breast cancer in post-menopausal women. The degree of risk increases proportionally with an increase in adiposity. There is mounting evidence that stromal cells in the tumor microenvironment make pivotal contributions to tumor progression. Stromal adipocytes have been shown to exert their influence on breast cancer cells via two secreted adipocytokines, leptin and adiponectin. Leptin stimulates proliferation and invasiveness of breast cancer cell lines. Conversely, adiponectin is down-regulated in obese individuals, and there is an inverse relationship between adiponectin levels and risk of breast cancer. Therefore, in breast cancer development, it is important to know if there are significant interactions or tumorigenic effects of excess adipose tissue on mammary epithelium. The question of how adipocytes exert their influence on pre-malignant mammary epithelial cells has not been resolved. Adiponectin was found to suppress the effects of oncogenic ras or Myc in p53-- MMECs. These cells slowed their rate of growth in response to adiponectin, and was better able to maintain genomic stability. This lead to reduced transformation potential in a soft agar assay. Conversely, the effects of leptin was very striking. The presence of p53 was able to suppress the oncogenic effects of ras and Myc. However, when leptin was present, oncogene-expressing WT-MMECs behaved just like p53-- MMECs. These cells had a greatly enhanced rate of growth and became highly aneuploid. Furthermore, p53 was no longer able to function as a tumor suppressor in the presence of leptin, allowing oncogenic transformation.