Blockade of cMYC oncogenic function by pregnancy-induced alterations and remodeling of the mammary gland

摘要/项目摘要 这项建议的目标是了解如何通过怀孕的过渡影响分子和细胞的 乳腺上皮细胞的状态和肿瘤发生。许多流行病学研究发现， 怀孕会改变患乳腺癌的风险。这些研究一致表明，足月妊娠 在25岁之前，与乳腺癌终生发病率下降三分之一有关。而 妊娠的保护作用已在啮齿动物癌症模型中得到验证，这是妊娠的潜在分子基础。 这一影响尚不清楚。 我们已经发现，怀孕导致MEC的表观基因组和增强子景观的持续变化。 使用可诱导的c-MYC小鼠模型，我们还发现肿瘤发生和转录输出 在妊娠后MEC中，该癌基因下游的表达减少。在本提案中，我们将调查 这些强大的表型背后的分子基础。我们将使用表观基因组学，体外，体内和生化 方法来确定如何通过怀孕调节c-MYC的转录功能。我们假设- MYC与辅因子和特定顺式调控元件的相互作用在该系统中被改变。 我们还将研究特定的染色质调节因子如何促进妊娠介导的表观基因组重连。 这些努力将建立在我们最近的数据上，这些数据表明EZH 2支持妊娠后表观基因组， 野生型小鼠。总的来说，这项研究将为乳腺癌的细胞生物学提供基本的见解。 腺和携带的发现，可以利用开发预防性治疗， 调节人类乳腺癌风险。

Abstract/Project Summary The goal of this proposal is to understand how transitions through pregnancy influence the molecular and cellular state of mammary epithelial cells and oncogenesis. Numerous epidemiological studies have found that pregnancy alters the risk of breast cancer. These studies have shown consistently that a full-term pregnancy prior to the age of 25 is associated with a one-third decrease in the life-time incidence of breast cancer. While a protective effect of pregnancy has been validated in rodent models of cancer, the underlying molecular basis for this effect remains unclear. We have found that pregnancy leads to persistent changes in the epigenome and enhancer landscape of MECs. Using an inducible c-MYC mouse model, we also find that oncogenesis and the transcriptional output downstream of this oncogene are reduced in post-pregnancy MECs. In this proposal we will investigate the molecular basis underlying these robust phenotypes. We will use epigenomics, ex vivo, in vivo and biochemical methods to define how the transcriptional function of c-MYC is modulated by pregnancy. We hypothesize that c- MYC interactions with cofactors and with specific cis-regulatory elements are altered in this system. We will also study how specific chromatin regulators contribute to pregnancy-mediated epigenomic rewiring. These efforts will build upon our recent data suggesting that EZH2 supports the post-pregnancy epigenome in wild-type mice. Collectively, this research will provide fundamental insights into the cell biology of the mammary gland and carry the potential for discoveries that could be harnessed to develop preventative treatments that modulate breast cancer risk in humans.