Pregnancy, Obesogenic Environments, and Basal-like Breast Cancer

描述（由申请人提供）：流行病学和实验数据表明，足月妊娠可降低乳腺癌风险。然而，最近的研究表明，虽然足月妊娠确实降低了雌激素受体和腔内乳腺癌的风险，但妊娠实际上可能增加更具侵袭性的基底样乳腺癌的风险。在观察人类数据集中，年龄、种族、胎次和肥胖之间存在复杂的关系，这使得很难将这些发现转化为公共卫生信息——肥胖和怀孕等行为变量通常是相关的。使用啮齿类动物的实验研究已经分别检查了胎次和肥胖，但到目前为止，胎次和肥胖的独立和共同影响还没有被解剖。这一建议将在肿瘤异质性的背景下解决这一差距，特别关注基底样乳腺癌亚型和微环境变化，这些变化在重要的易感性窗口期（产后期）促进了这种乳腺癌亚型。在目的1中，我们将使用小鼠基底样和异质性乳腺癌模型来研究妊娠和高脂肪饮食对肿瘤的促进作用。终点将包括肿瘤潜伏期、肿瘤质量、基因表达和怀孕和/或肥胖引起的microRNA变化。巨噬细胞浸润是癌症进展和肥胖发病的一个重要变量，将在形成的肿瘤的微环境中被表征。在目标2中，共培养系统将用于模拟肥胖和妊娠相关巨噬细胞浸润对基底样和腔内乳腺癌的影响。在目标3中，研究人员将从正在进行的乳房微环境研究中对正常乳腺组织进行辅助组织学和表达研究，并利用母体研究中可用的基因表达和人口统计学信息进行分析。比较体外和体内系统以及跨物种的结果将有助于确定在基底样微环境中受胎次和肥胖差异调节的最重要的途径和/或生物标志物。在目标4中，调查人员将确定和解决其目标人口的知识需求，并通过国家倡导者网络传播外联工具。

DESCRIPTION (provided by applicant): Epidemiologic and experimental data have shown that a full term pregnancy reduces breast cancer risk. However, recent studies have suggested that while full term pregnancy does reduce risk for estrogen receptor and luminal breast cancers, pregnancy may actually increase risk of more aggressive basal-like breast cancers. There are complex relationships between age, race, parity, and obesity in observational human datasets making it difficult to translate these findings into public health messages - behavioral variables such as obesity and pregnancy are often correlated. Experimental studies using rodents have examined parity and obesity individually, but to date, the independent and joint effects of parity and obesity have not been dissected. This proposal will address this gap and will do so within the context of tumor heterogeneity, focusing specifically on the basal-like breast cancer subtype and the microenvironment changes that promote this breast cancer subtype during a vital window of susceptibility, the post partum period. In aim 1, mouse models of basal-like and heterogeneous breast cancer will be used to study the tumor promoting effects of pregnancy and high fat diet. Endpoints will include tumor latency, tumor mass, gene expression and microRNA changes induced by pregnancy and/or obesity. Macrophage infiltration, an important variable in cancer progression and obesity pathogenesis will be characterized in the microenvironment of the tumors that form. In aim 2, a co-culture system will be used to model the effects of obesity- and pregnancy-associated macrophage infiltration on basal-like and luminal breast cancers. In aim 3, the investigators will conduct ancillary histology and expression studies on normal breast tissue from an ongoing study of breast microenvironment and utilize available gene expression and demographic information from that parent study in their analyses. Comparison of results across in vitro and in vivo systems and across species will help to identify the most important pathways and/or biomarkers that are differentially regulated by parity and obesity in the basal-like microenvironment. In aim 4, the investigators will identify and address the knowledge needs of their target population and disseminate outreach tools through a network of national advocates.