Abstract 5937: Obesity-induced destabilization of p16INK4A promotes the procarcinogenic effects of breast stromal adipocytes through miR-141/miR-146b-5p-dependent inhibition of leptin

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Abstract Obesity, a disease linked to increased number of adipocytes in various tissues, is increasingly recognized as a risk factor for the development of breast cancer. However, the molecular basis of adipocyte-related breast carcinogenesis remains elusive. In this study, we established and characterized normal stromal adipocytes from post-plastic surgery of breast tissues from obese and lean women. We have shown that adipocytes from obese women express low level of the tumor suppressor p16 protein, have higher secretion of various adipokines and higher invasion and migration capabilities as compared to adipocytes from lean women. In addition, down-regulation of p16INK4A by shRNA in adipocytes from lean women increased the expression/secretion levels of various adipokines including leptin, activated breast adipocytes and enhanced their migration/invasion abilities. Consequently, media conditioned with p16-deficient adipocytes or adipocytes from obese women promote epithelial-to-mesenchymal-transition in normal breast luminal cells in a leptin-dependent manner and induced tumor growth in vivo. Indeed, p16INK4A suppresses Leptin at the mRNA level through miR-141 and miR-146b-5p, which inhibits Leptin expression through a specific sequence at the Leptin 3’UTR. These results show the existence of active adipocytes in the mammary gland of obese women in absence of breast cancer cells and provide the first indication that p16INK4A through targeting miR-141 and miR-146b-5p suppresses Leptin and its procarcinogenic effects. This indicates that p16 pathway has non-cell-autonomous tumor suppressor function in breast stromal adipocytes. Note: This abstract was not presented at the meeting. Citation Format: Huda H. Alkhalaf, Abdelilah Aboussekhra. Obesity-induced destabilization of p16INK4A promotes the procarcinogenic effects of breast stromal adipocytes through miR-141/miR-146b-5p-dependent inhibition of leptin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5937. doi:10.1158/1538-7445.AM2017-5937