Metabolic reprogramming in breast cancer

摘要/摘要 作为一种多功能细胞因子，LIF在肿瘤发生中具有复杂的作用。虽然LIF抑制白血病，最近 包括我们的研究表明LIF促进许多类型的实体瘤的发展和进展， 包括乳腺癌LIF在不同的乳腺癌中经常过表达（约50-60%）。 亚型，并在45岁以下女性的乳腺癌中富集，这往往是更具侵略性的， 较少的治疗选择。LIF过度表达与不良预后相关。然而， LIF在乳腺癌中的作用尚未得到很好的确立，其潜在机制也知之甚少。代谢 重编程是癌细胞的标志，也是癌症进展的关键因素，包括乳腺癌。 癌糖酵解增强和脂质合成增强是癌症中的两个关键代谢变化，包括 乳腺癌，这是癌症进展的关键。我们使用公正方法进行的初步研究 （液相色谱/质谱为基础的代谢物分析）确定LIF作为一种新的和独特的 乳腺癌中代谢重编程的驱动因素。我们发现：1）LIF激活糖酵解和脂质 2）通过RNAi阻断糖酵解和脂质合成， 特异性药物抑制剂在很大程度上消除了LIF对乳腺肿瘤发生的促进作用。 基于我们的初步结果，我们假设LIF在乳腺肿瘤发生中起关键作用， 糖酵解和脂质合成的增强是一种关键的潜在机制，其可以作为治疗的靶点。 为了验证这一假设，我们提出了一个严格的研究计划，采用稳健和无偏的方法。我们将（1） 通过建立LIF转基因和基因敲除小鼠模型，研究LIF在乳腺肿瘤发生中的作用 小鼠模型; 2）确定由LIF驱动的代谢重编程是否是一种关键机制， LIF促进乳腺肿瘤发生; 3）评估靶向这些代谢变化的治疗潜力， LIF过表达的乳腺癌。本研究的目的是确定LIF在肿瘤细胞中的作用和机制。 乳腺癌和代谢重编程为乳腺癌提供有效的治疗靶点/策略 癌如果成功，这项研究将：1）提供LIF促进乳腺肿瘤发生的证据; 2）揭示 LIF作为乳腺癌中代谢重编程的重要和独特驱动因素; 3）揭示了乳腺癌的机制。 LIF在乳腺肿瘤发生和代谢重编程中的作用; 4）提供靶向治疗的原理和策略 LIF过表达的乳腺癌中的特异性代谢变化。

Summary/Abstract As a multifunctional cytokine, LIF has a complex role in tumorigenesis. While LIF inhibits leukemia, recent studies including ours show that LIF promotes the development and progression of many types of solid tumors, including breast cancer. LIF is frequently overexpressed in breast cancers (~50-60%) across different subtypes, and is enriched in breast cancers in women younger than 45, which tend to be more aggressive with less treatment options. LIF overexpression is associated with poor prognosis. However, the precise role of LIF in breast cancer is not well-established and its underlying mechanism is poorly understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression, including breast cancer. Enhanced glycolysis and enhanced lipid synthesis are two key metabolic changes in cancer, including breast cancer, which are critical for cancer progression. Our preliminary studies using an unbiased approach (liquid chromatography/mass spectrometry-based metabolite analysis) identified LIF as a novel and unique driver for metabolic reprogramming in breast cancer. We found that: 1) LIF activates glycolysis and lipid synthesis in breast cancer cells in vitro and in vivo; 2) blocking glycolysis and lipid synthesis by RNAi and specific pharmacological inhibitors largely abolished the promoting effect of LIF on breast tumorigenesis. Based on our preliminary results, we hypothesize that LIF plays a critical role in breast tumorigenesis, and enhanced glycolysis and lipid synthesis is a critical underlying mechanism, which can be targeted for therapy. To test this hypothesis, we proposed a rigorous research plan with robust and unbiased methods. We will 1) establish LIF's role in breast tumorigenesis by using 3 mouse models, including LIF transgenic and knockout mouse models; 2) determine whether metabolic reprograming driven by LIF, is a critical mechanism whereby LIF promotes breast tumorigenesis; 3) assess the therapeutic potential of targeting these metabolic changes in breast cancer with LIF overexpression. The goal of this study is to determine the role and mechanism of LIF in breast cancer and metabolic reprogramming to provide effective therapeutic targets/strategies for breast cancer. If successful, this study will: 1) provide evidence that LIF promotes breast tumorigenesis; 2) uncover LIF as an important and unique driver for metabolic reprogramming in breast cancer; 3) reveal mechanisms for LIF in breast tumorigenesis and metabolic reprogramming; 4) provide the rationale and strategies to target specific metabolic changes in breast cancers with LIF overexpression.