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

说明(申请人提供)：乳腺的生长和发育是在与生殖发育密切相关的循环激素和旁分泌信号的影响下发生的。青春期乳腺的发育依赖于雌激素，因此摘除卵巢会暂停所有乳腺的生长。与此同时，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。我们有一个重要的发现，反式-10，顺-12共轭亚油酸(10，12 CLA)是一种特殊的膳食脂肪，可以在没有雌激素的情况下刺激乳腺生长，而且不依赖雌激素受体。类似地，我们证明了10，12共轭亚油酸在人类乳腺癌转基因小鼠模型中刺激了肿瘤的形成。同时，饮食中的10，12共轭亚油酸诱导全身代谢变化，包括肝脏脂肪堆积、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，通过生长因子受体传递的信号可能参与了10，12共轭亚油酸诱导的乳腺生长。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。我建议测试一种假设，即特定的生长因子信号网络对这种饮食脂肪刺激的雌激素非依赖性乳房生长负责。我将首先建立乳腺对饮食10，12共轭亚油酸的时间反应。接下来，我将检测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养10，12共轭亚油酸的去卵巢小鼠的乳腺中过度表达。这些研究旨在为雌激素非依赖性乳腺癌的治疗确定新的靶点，并强调饮食可能促进乳腺肿瘤发生的潜在机制。

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.