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管腔乳腺癌的风险，但妊娠实际上可能会增加更具侵袭性的基底样乳腺癌的风险。在观察性人类数据集中，年龄、种族、产次和肥胖之间存在复杂的关系，因此很难将这些发现转化为公共健康信息-肥胖和怀孕等行为变量通常是相关的。使用啮齿动物的实验研究已经单独检查了产次和肥胖，但迄今为止，产次和肥胖的独立和联合影响尚未被解剖。该提案将解决这一差距，并将在肿瘤异质性的背景下这样做，特别关注基底样乳腺癌亚型和微环境的变化，促进这种乳腺癌亚型在一个重要的窗口期的易感性，产后时期。目的一：利用小鼠基底细胞样和异质性乳腺癌模型，研究妊娠和高脂饮食对乳腺癌的促癌作用。终点将包括肿瘤潜伏期、肿瘤质量、基因表达和妊娠和/或肥胖诱导的microRNA变化。巨噬细胞浸润是癌症进展和肥胖发病机制中的重要变量，其特征在于形成的肿瘤的微环境。 在目标2中，将使用共培养系统来模拟肥胖和妊娠相关的巨噬细胞浸润对基底样和管腔型乳腺癌的影响。在目标3中，研究者将对正在进行的乳腺微环境研究中的正常乳腺组织进行辅助组织学和表达研究，并在其分析中利用母研究中的可用基因表达和人口统计学信息。跨体外和体内系统以及跨物种的结果比较将有助于确定在基础样微环境中由奇偶性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，调查人员将确定和满足目标人群的知识需求，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.