糖脂代谢途径异常活化是肿瘤细胞的标志，作为甾体反应元件结合蛋白1（SREBP1）转录调控的主要靶点，酰基辅酶A去饱和酶1（SCD1）是糖脂代谢的最后限速步骤。尽管SCD1过表达已在多种肿瘤中证实，但在乳腺癌发生中的作用及作用机制以及特异性干涉SCD1是否对乳腺癌的发生发展有抑制作用仍不明确。我们前期研究发现：①Her2/Neu阳性乳腺癌组织SCD1高表达；②Her2转化的乳腺上皮细胞SREBP1活性增强，同时SCD1表达增高；③活化的PPARγ可促进Her2诱导的肿瘤发生。本项目拟在Her2阳性人乳腺癌组织检测SREBP1、SCD1及PPARγ的表达；检测Her2/shSCD1乳腺上皮细胞/乳腺癌细胞系、Her2/shSCD1 及 Her2/scd1-/-小鼠模型中SREBP1及PPARγ对SCD1的调控作用。明确Her2通过SREBP1及PPARγ对SCD1的活化是乳腺癌重要发病机制。

Tumor cells utilize glucose more efficiently than normal cells to produce saturated fatty acids (SFAs) and mono-unsaturated fatty acids (MUFAs) in order to sustain the great demand for membrane phospholipids，which makes the enhanced lipogenesis a common feature and a metabolic hallmark of rapidly proliferating tumor cells. Stearoyl-CoA desaturases 1 (SCD1), one of the major transcriptional targets of sterol response element-binding protein-1 (SREBP1), controls the production of MUFAs through catalytic conversion of SFAs. Elevated expression/activity of SCD1 have been reported in a variety of cancer types, however the role and the underlying mechanisms of SCD1's involvement in breast tumorigenesis and whether targeting lipogenic signaling intervenes with breast cancer (BC) progression still lack adequate understanding. Our preliminary results showed that interrogation of >900 BC patients' tumors identified a Her2/Neu (also known as ErbB2 ) subtype that overexpressed SCD1, and that oncogenic transformation of breast epithelial cells by Her2 leads to SREBP1 activation and increased SCD1 expression. We also found that activation of peroxisome proliferator-activated receptor gamma (PPARγ) enhances Her2-induced tumorigenesis and induces SCD1 expression in BC. Based on these data, we will firstly determine the protein expression of SREBP1, SCD1 and PPARγ in Her2 positive type of BC by immunohistochemistry (IHC) staining. Statistical analyses will be carried out to evaluate the association between their expression and several clinical parameters. Secondly, we will determine the regulating role of SREBP1 and PPARγ on SCD1 in Her2/shSCD1 breast epithelial cells/breast cancer cells, Her2/shSCD1 and Her2/scd1-/- mice models.The objective of this proposal is to determine the role and the underlying mechanisms of SREBP1 and PPARγ on SCD1 in breast tumorigenesis.

糖脂代谢途径异常活化是肿瘤细胞的标志，作为甾体反应元件结合蛋白1（SREBP1）转录调控的主要靶点，酰基辅酶A去饱和酶1（SCD1）是糖脂代谢的最后限速步骤。我们前期研究发现：①HER2/Neu阳性乳腺癌组织SCD1高表达；②HER2转化的乳腺上皮细胞SREBP1活性增强，同时SCD1表达增高；③活化的PPARγ可促进HER2诱导的肿瘤发生。本项目通过临床乳腺癌大样本的检测分析，发现人乳腺癌组织中SCD1高表达，且存在强的异质性，主要高表达在HER2阳性病例。进一步通过HER2/shSCD1乳腺上皮细胞/乳腺癌细胞系、HER2/shSCD1 及 her2/scd1-/-小鼠模型证实Her2通过SREBP1及PPARγ对SCD1的活化是乳腺癌重要发病机制。HER2-PPARγ- SREBP1-SCD1的调控途径可成为潜在的HER2阳性乳腺癌治疗靶点。同时由于PPARγ激活是HER2诱发乳腺癌发生的重要分子机制，提示II型糖尿病患者使用PPARγ激动剂时需慎重。