肥胖影响雌激素受体阳性乳腺癌预后机制研究

Now that obesity and breast cancer rates are skyrocketing, the need to understand this link has become far more urgent. Obesity has a significant negative impact on breast cancer, and obesity is a modifiable factor in the prognosis of breast cancer. Recent research has demonstrated that the insulin/IGF-1, estrogen and adipokine signaling pathways may mediate the effects of obesity on breast cancer. There is synergistic crosstalk/interaction between the insulin/IGF-1 and estrogen signaling pathways. Our preliminary results show that some obesity treatments have direct inhibitory effects on breast cancer cells. We hypothesize that specific obesity treatments can improve survival of obese breast cancer subjects by their effects on insulin/IGF-1, adipokine, and estrogen signaling. We shall test this hypothesis in mouse models. We propose to use the MMTV-TGF-α model of ER-positive breast cancer and crossbreed this transgenic model with a monogenic model of obesity (Ay/a) and a monogenic model of the metabolic syndrome (FGFR4 -/-) in two separate sets of experiments. These models of ER-positive breast cancer with two different levels of obesity will allow us to investigate the differential benefits of various treatments (placebo, caloric restriction, metformin, pioglitazone, metformin combined pioglitazone) aimed at obesity and its associated insulin resistance.Serum markers, hormones and adipokines will be measured and a Cox proportional hazards model will be fitted to the data to assess the effect of these factors such as treatment medications, hormones, glycohemoglobin, and adipokines on the survival among these groups. We shall determine if any treatments of obesity or related signaling can improve survival in mouse models of obeisty and breast cacner. We also shall determine the impact of obesity on angiogenesis, proliferation and apoptosis of breast cancer that may lead to tumor progression by comparing breast cancer samples from obese mice with those from lean mice. The animal studies will generate data and new hypotheses that can lead to future clinical trials that result in patient benefits within 10 years.

乳腺癌及肥胖发病率显著升高，乳腺癌伴有肥胖患者比例也进一步增大，而肥胖减少乳腺癌患者生存期。所以，研究肥胖影响乳腺癌预后机制对该类患者治疗意义重大。肥胖与乳腺癌预后关系涉及胰岛素耐受，外周脂肪组织中雌激素芳香化以及脂肪细胞因子直接作用，目前推测至少三条信号通路（胰岛素/IGF-1通路，脂肪细胞因子和雌激素）与之相关。培育繁殖不同程度肥胖雌激素受体（ER）阳性乳腺癌小鼠模型MMTV-TGF-ɑ:FGFR4-/-及MMTV-TGF-ɑ:Ay/a及正常体重乳腺癌小鼠模型MMTV-TGF-ɑ:FGFR4+/+，并给予二甲双胍、吡咯列酮等干预措施，检测各信号通路相关指标，明确肥胖对雌激素受体阳性乳腺癌细胞增殖，凋亡及血管生成的影响;进行生存分析及Cox比例风险模型评估干预因素，激素水平，代谢参数及体脂比等对乳腺癌小鼠预后影响。本研究将明确哪种信号通路或药物参与或改善ER阳性肥胖乳腺癌预后。

目的：乳腺癌发病率高，治疗方案多种，哪种治疗方案能够延长乳腺癌生存期。方法：249个乳腺癌患者，分别接受两种药物治疗方案。通过肿瘤坏死率/毒性及生存期评价两种药物治疗方案的优劣性。结果：PH-FECH化疗方案较TCH化疗方案疗效好，血液毒性低，耐受性好，但神经毒性较大。