"Mechanisms of diet-induced, estrogen-independent mammary growth"

“饮食诱导的、不依赖雌激素的乳房生长机制”

• 批准号: 8783117
• 负责人: Grace Ellen Berryhill
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783117
• 关键词: Breast Epithelial Cells; Complex; Conjugated Linoleic Acids; Consumption; Cues; Data; Development; Diet; Dietary Component; Dietary Fats; Ductal; EGFR inhibition; Employee Strikes; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cell Proliferation; Epithelium; ErbB Receptor Family Protein; Estrogen Receptors; Estrogens; Event; Excision; Experimental Models; Family; Fatty acid glycerol esters; Gene Expression; Genome; Goals; Growth; Growth Factor; Growth Factor Receptors; Growth and Development function; Hormones; Human; Inflammation; Inflammatory; Insulin; Insulin Resistance; Ligands; Lipids; Liver; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Measures; Mediating; Metabolic; Metabolic syndrome; Mitogens; Modeling; Molecular; Mus; Obesity; Ovary; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Proliferating; Proteins; Puberty; RNA Sequences; Research Project Grants; Role; Serum; Signal Transduction; Signaling Molecule; System; Technology; Testing; Time; Transcript; Transgenic Mice; cancer risk; cancer therapy; cytokine; expectation; feeding; insight; liver inflammation; mRNA Expression; malignant breast neoplasm; mammary gland development; mouse model; new therapeutic target; novel; paracrine; prevent; protein expression; public health relevance; receptor; reproductive development; research study; response; transcriptomics; tumorigenesis

DESCRIPTION (provided by applicant): Growth and development of the mammary glands occurs under the influence of circulating hormones and paracrine cues closely aligned with reproductive development. Development of the mammary glands during puberty is estrogen-dependent, whereby removal of the ovaries suspends all mammary growth. In parallel, a growing body of evidence suggests that diet can promote growth of the mammary glands, which may increase breast cancer risk. We have made the important finding that trans-10, cis- 12 conjugated linoleic acid (10, 12 CLA), a specific dietary fat, can stimulate the mammary glands to grow in the absence of estrogen and independent of the estrogen receptor. Similarly, we demonstrated that 10, 12 CLA stimulates tumorigenesis in a transgenic mouse model of human breast cancer. In parallel, dietary 10, 12 CLA induces whole-body metabolic changes including fat accumulation in the liver, inflammation, elevated insulin levels, and insulin resistance. Importantly, our data indicate that signaling via growth factor receptors may be responsible for mediating mammary growth induced by 10,12 CLA. Intriguingly, these same pathways have been implicated in in aggressive, estrogen-independent breast cancers. I propose to test the hypothesis that specific growth factor signaling networks are responsible for estrogen-independent mammary growth stimulated by this dietary fat. I will first establish the temporal response of the mammary glands to dietary 10, 12 CLA. Next, I will examine the protein and mRNA expression levels of specific growth factor signaling molecules. Lastly, I will use cutting edge RNA-sequencing technology to probe downstream signaling networks that may be over-represented in the mammary glands of ovariectomized mice fed 10,12 CLA. These studies stand to identify new targets for the treatment of estrogen-independent breast cancers and to highlight potential mechanisms of how diet might promote mammary tumorigenesis.

描述（由申请方提供）：乳腺的生长和发育在与生殖发育密切相关的循环激素和旁分泌线索的影响下发生。青春期乳腺的发育依赖于雌激素，切除卵巢会使所有乳腺发育暂停。同时，越来越多的证据表明，饮食可以促进乳腺的生长，这可能会增加乳腺癌的风险。我们已经取得了重要的发现，反式-10，顺式-12共轭亚油酸（10，12 CLA），一种特殊的膳食脂肪，可以刺激乳腺生长，在缺乏雌激素和独立的雌激素受体。同样，我们证明了10，12 CLA刺激人乳腺癌的转基因小鼠模型中的肿瘤发生。同时，膳食10，12 CLA诱导全身代谢变化，包括肝脏中的脂肪积累、炎症、胰岛素水平升高和胰岛素抵抗。重要的是，我们的数据表明，通过生长因子受体的信号传导可能是负责介导的10，12 CLA诱导的乳腺生长。有趣的是，这些相同的途径与侵袭性、雌激素非依赖性乳腺癌有关。我建议测试的假设，即特定的生长因子信号网络负责雌激素非依赖性乳腺生长刺激这种膳食脂肪。我将首先建立乳腺对膳食10，12共轭亚油酸的时间反应。接下来，我将检查特定生长因子信号分子的蛋白质和mRNA表达水平。最后，我将使用尖端的RNA测序技术来探测下游信号网络，这些信号网络可能在喂食10，12 CLA的卵巢切除小鼠的乳腺中过度表达。这些研究旨在确定治疗雌激素非依赖性乳腺癌的新靶点，并强调饮食如何促进乳腺肿瘤发生的潜在机制。