Alcohol Effect on Human Breast Cancer Microenvironment

描述（由申请人提供）：大量饮酒使人类乳腺癌的风险增加高达50%，并且与已经诊断的患者的预后更差和复发率更高相关。这些观察结果表明，酒精可能在启动和进展阶段都起作用。大约75%的乳腺癌病例是散发性的，强调需要识别和调节导致疾病发生和进展的环境和/或营养风险因素。酒精导致乳腺癌风险增加的机制尚不清楚。长期饮酒主要通过炎症和氧化应激介导其对各种器官系统的影响。乳腺癌的发生和发展与局部炎性细胞因子环境有关，酒精可能通过对乳腺组织的促炎作用发挥其作用。癌症进展和肿瘤微环境的特征在于氧化应激和蛋白质稳态的不平衡。酒精激活应激诱导的热休克转录因子（HSF 1）及其靶基因，热休克蛋白（hsps），在巨噬细胞和乳腺癌上皮细胞中的蛋白质稳态中是重要的。Hsps作为炎症过程中的分子伴侣，HSF1也可以直接诱导独特的基因集，如细胞因子和趋化因子，以刺激肿瘤的发生和促进侵袭，从而有助于更具侵略性的表型。这项研究的中心假设是，酒精直接-通过激活应激介导的HSF1和/或诱导hsps-协调炎症微环境，有助于体内人类乳腺癌的发生和发展。我们将使用体外细胞培养研究和人类乳腺癌外植体的新型小鼠模型相结合，以确定长期饮酒对人类癌症生长，进展和转移的影响。该小鼠模型的独特之处在于能够接受人肿瘤异种移植物，其维持与原始亲本肿瘤相似的架构结构、人免疫细胞、人基质和肿瘤微环境。这个强大的模型将允许在功能正常的哺乳动物系统中操纵单一因素（如酒精），同时控制人类研究中常见的其他混杂因素。为了确定机制，我们将研究HSF1激活，HSF1靶向热休克蛋白基因，以及确定独特的诱导细胞因子和趋化因子基因的关键，以维持乳腺肿瘤发生过程中的炎症环境。这些研究将建立一种新的体内动物模型来研究酒精对人类乳腺癌的影响，也将揭示压力介导的调节乳腺癌炎症的新机制。

DESCRIPTION (provided by applicant): Heavy alcohol consumption increases the risk of human breast cancer by up to 50% and is associated with a worse outcome and a higher incidence of relapse in those where a diagnosis is already made. These observations suggest that alcohol may function both at the initiation and progression stages. Approximately 75% of breast cancer cases are sporadic, stressing the need to identify and modulate environmental and/or nutritional risk factors responsible for disease initiation and progression. The mechanism by which alcohol contributes to an increased breast cancer risk is not clear. Prolonged alcohol consumption primarily mediates its effects in various organ systems via inflammation and oxidative stress. Initiation and progression of breast cancer is linked to a local inflammatory cytokine environment and it is likely that alcohol exerts its affect via a pro-inflammatory effect n the breast tissue. Cancer progression and the tumor microenvironment are characterized by an imbalance in oxidative stress and protein homeostasis. Alcohol activates stress induced heat shock transcription factor (HSF1) and its target genes, heat shock proteins (hsps) which are important in proteostasis, in macrophages and in breast cancer epithelial cells. Hsps serve as molecular chaperones in inflammatory processes and HSF1 may also directly induce unique gene sets such as cytokines and chemokines to stimulate tumor initiation and promote invasion thus contributing to a more aggressive phenotype. The central hypothesis of this grant is that alcohol directly - via activation of stress mediated HSF1 and/or induction of hsps - orchestrates an inflammatory microenvironment conducive to initiation and progression of human breast cancer in vivo. We will use a combination of in vitro cell culture studies and novel mouse model of human breast cancer ex-plants to determine the effects of chronic alcohol consumption on human cancer growth, progression and metastasis. The unique aspects of this mouse model is the ability to accept human tumor xenografts which maintain architectural structure, human immune cells, human stroma a tumor microenvironment similar to the original parent tumor. This powerful model will allow manipulation of single factors (such as alcohol) in a functioning mammalian system, while controlling other confounding factors common to human studies. To determine mechanisms, we will examine HSF1 activation, HSF1 target hsp genes as well as identify unique induction of cytokine and chemokine genes crucial to maintain inflammatory environment during breast tumorigenesis. These studies will establish a novel in vivo animal model to investigate the effects of alcohol on human breast cancer and will also uncover stress- mediated novel mechanisms regulating inflammation in breast cancer.