Regulation of lipid synthesis in estrogen receptor positive breast cancer

雌激素受体阳性乳腺癌中脂质合成的调节

基本信息

批准号：
9296091
负责人：
Jonna Frasor
金额：
$ 36.5万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296091
关键词：
Adipose tissue Adverse drug effect Bioinformatics Biological Breast Cancer Cell Breast Cancer cell line Breast cancer metastasis Cell Line Cell Proliferation Cell membrane Cells Cholesterol Clinical Data Disease Down-Regulation Endocrine Enzymes Estradiol Estrogen Receptor alpha Estrogen receptor positive FOXO1A gene Fatty Acids Fatty-acid synthase Genes Genetic Transcription Growth Growth Factor Heel Hormonal Hormones Human Insulin-Like Growth Factor I Lipid Synthesis Pathway Lipids Liver Malignant Neoplasms Mammary Neoplasms Membrane Modeling Nature Pathway interactions Patients Process Production Proteins Recurrence Recurrent tumor Regulation Repression Resistance Resistance development Role Signal Transduction Signaling Molecule Specimen Testing Therapeutic Tissues Tumor Cell Invasion Tumor-Derived Up-Regulation Woman Work base hormone regulation hormone therapy insight lipid biosynthesis lipid mediator malignant breast neoplasm new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics public health relevance response targeted cancer therapy targeted treatment transcription factor tumor tumor growth tumor metabolism tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Alterations in cancer cell metabolism are thought to represent an important "Achille's heel" that can be exploited for developing targeted cancer therapies. In particular, de novo lipogenesis (DNL) is increasingly recognized as an essential pathway for cancer growth due to its role in generating new cell membranes and signaling molecules. However, little is known about what regulates DNL in cancers. We propose that a greater understanding of i) the factors and mechanisms controlling DNL and ii) the nature and function of lipid products of DNL will provide new therapeutic strategies to target DNL and treat recurrent/resistant ER+ breast cancers. Using a variety of approaches and models, we have established that SREBP1 and 2, the master transcriptional regulators of fatty acid and cholesterol synthesis, respectively, regulate key enzymes for lipid synthesis, as well as DNL itself, in endocrine sensitive and resistant estrogen receptor positive breast cancer cells. Moreover, SREBP activity is essential for i) hormone-dependent proliferation of ER+ breast cancer cells that are sensitive to endocrine therapy, ii) hormone-independent proliferation of endocrine-resistant ER+ breast cancer cells, and iii) invasion of endocrine-resistant cells. We find that SREBP expression and activity are hormonally regulated by estradiol (E2) and/or the growth factor IGF-1 in several ER+ breast cancer cell lines. Additionally, we have identified two potential mechanisms by which E2 and IGF-1 may regulate SREBPs expression and activity. Based on these findings, we hypothesize that hormonal regulation of SREBP expression and activity leads to de novo synthesis of specific lipid mediators that are essential for tumor growth in endocrine-sensitive and resistant breast cancers. To test this hypothesis, we propose to conduct studies in in cell line-derived and patient-derived tumor xenografts to 1) define the function of SREBP activity in ER+ breast tumors, 2) identify biologically important lipid products of DNL, and 3) investigate hormonal regulation of DNL in growing ER+ breast tumors. Together, the results of these studies will advance our understanding of the regulation and function of DNL in breast cancer, including differences between ER+ cancers that are sensitive or resistant to endocrine-therapy. By gaining a deeper understanding of these differences, our work will provide a compelling basis for developing novel therapeutic strategies to target DNL and its lipid products in recurrent/resistant ER+ breast cancers.

描述（由申请人提供）：癌细胞代谢的改变被认为是可用于开发靶向癌症疗法的重要“致命弱点”。特别是，从头脂肪生成（DNL）越来越被认为是癌症的重要途径。然而，我们对癌症中 DNL 的调节因素知之甚少。 DNL 脂质产物的性质和功能将为靶向 DNL 和治疗复发/耐药 ER+ 乳腺癌提供新的治疗策略。使用多种方法和模型，我们已经确定了 SREBP1 和 2，脂肪酸和胆固醇的主要转录调节因子。在内分泌敏感和耐药的雌激素受体阳性乳腺癌细胞中，SREBP 活性分别调节脂质合成的关键酶以及 DNL 本身。此外，SREBP 活性对于 i) ER+ 乳腺癌细胞的激素依赖性增殖至关重要。对内分泌治疗敏感的细胞，ii) 内分泌耐药 ER+ 乳腺癌细胞的激素依赖性增殖，以及 iii) 内分泌耐药细胞的侵袭，我们发现 SREBP 的表达和活性受雌二醇 (E2) 和/或激素的调节。此外，我们还基于这些发现了 E2 和 IGF-1 调节 SREBP 表达和活性的两种潜在机制。研究结果表明，SREBP 表达和活性的激素调节会导致肿瘤生长所必需的特定脂质介质的从头合成为了检验这一假设，我们建议在细胞系来源和患者来源的肿瘤异种移植物中进行研究，以 1) 确定 SREBP 活性在 ER+ 乳腺肿瘤中的功能，2) 识别生物学上重要的脂质。 DNL 的产品，以及 3) 研究 ER+ 乳腺肿瘤中 DNL 的激素调节，这些研究的结果将促进我们对乳腺癌中 DNL 的调节和功能的理解，包括差异。通过更深入地了解这些差异，我们的工作将为开发针对复发/耐药 ER+ 乳腺癌的 DNL 及其脂质产物的新治疗策略提供令人信服的基础。