Al-Khalaf Huda H, Amir Mrad, Al-Mohanna Falah, Tulbah Asma, Al-Sayed Adher, Aboussekhra Abdelilah
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.
The National Center for Genomics Research, King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia.
Mol Cell Biol. 2017 Aug 11;37(17). doi: 10.1128/MCB.00101-17. Print 2017 Sep 1.
Obesity is increasingly recognized as a risk factor for breast cancer development. However, the molecular basis of obesity-related breast carcinogenesis remains elusive. In this study, we have shown that obesity reduces the level of the tumor suppressor p16 protein in breast adipocytes, which showed active features and strong procarcinogenic potential both and in orthotopic tumor xenografts compared to mature adipocytes from lean women. Furthermore, obesity triggered epithelial-to-mesenchymal transition (EMT) in breast ductal epithelial cells. Interestingly, specific downregulation of p16 increased the expression/secretion levels of various adipokines, including leptin, and activated breast adipocytes from lean women. Consequently, like breast adipocytes from obese women, p16-deficient adipocytes induced EMT in normal primary breast luminal cells in a leptin-dependent manner and enhanced tumor growth. Additionally, we have shown that p16 negatively controls leptin at the mRNA level through microRNAs 141 and 146b-5p (miR-141 and miR-146b-5p), which bind the leptin mRNA at a specific sequence in the 3' untranslated region (UTR). These results show that obesity activates breast stromal adipocytes through p16 downregulation, which upregulates leptin and promotes procarcinogenic processes.
肥胖日益被认为是乳腺癌发生的一个风险因素。然而，肥胖相关的乳腺癌发生的分子基础仍不清楚。在本研究中，我们发现肥胖会降低乳腺脂肪细胞中肿瘤抑制因子p16蛋白的水平，与瘦女性的成熟脂肪细胞相比，这些脂肪细胞表现出活跃的特征和强大的促癌潜力，在原位肿瘤异种移植中也是如此。此外，肥胖会引发乳腺导管上皮细胞的上皮-间质转化（EMT）。有趣的是，p16的特异性下调会增加包括瘦素在内的各种脂肪因子的表达/分泌水平，并激活瘦女性的乳腺脂肪细胞。因此，与肥胖女性的乳腺脂肪细胞一样，p16缺陷型脂肪细胞以瘦素依赖的方式诱导正常原代乳腺管腔细胞发生EMT，并促进肿瘤生长。此外，我们还发现p16通过微小RNA 141和146b-5p（miR-141和miR-146b-5p）在mRNA水平上负调控瘦素，这两种微小RNA在3'非翻译区（UTR）的特定序列处与瘦素mRNA结合。这些结果表明，肥胖通过下调p16激活乳腺基质脂肪细胞，上调瘦素并促进致癌过程。
