Characterization of metastasis models derived from breast cancer patients of African descent

乳腺癌发生在八分之一的女性中，每年约有40，000人死亡 在美国有不同类型的乳腺肿瘤具有不同的治疗选择和结果。 三阴性乳腺癌（TNBC）缺乏雌激素和孕激素受体（ER和PR），不表达 HER2癌基因，并且已知是高度转移性的。由于他们缺乏ER，他们不能被靶向 抗雌激素，并且由于没有扩增HER2，靶向这种蛋白质的药物是无效的。的人 非洲血统（AA）的人被诊断为基底细胞样TNBC的可能性是人类的两到三倍。 欧洲血统，这是一个主要的差异，并有助于显着不良预后。鉴于 遗传因素已被确定为AA患者预后不良的预兆，我们假设AA 衍生的肿瘤细胞具有独特的亲和性，可用于治疗益处。这个目标 R21项目是完善来自AA患者的转移模型系统，因为它们目前缺乏 丰富和确定新的治疗选择，可能最有利于他们。该计划将（1）发展 来自AA TNBC患者来源的异种移植物的可跟踪转移模型，（2）定义它们的器官向性，（3） 在单细胞水平上对它们进行基因组学表征，以及（4）鉴定和测试可能 除了标准的化疗药物外，该研究通过其多方面的创新 方法和意义，因为它将直接解决一个主要的差距，并提供扩大测试的选择 可以立即在临床上使用的治疗方法。这些努力的预期结果是， 将开发模型系统，可以与更广泛的研究社区共享，并确定基因组 这些特征在转移中被激活并可以被靶向。实现这些目标将产生积极影响 关于差异研究和乳腺癌治疗。

Project Summary: Breast cancers arise in one out of eight women and account for ~40,000 deaths each year in the United States. There are different types of breast tumors with varied treatment options and outcomes. Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors (ER and PR), do not express the HER2 oncogene, and are known to be highly metastatic. Since they lack ER, they cannot be targeted with antiestrogens, and by not having amplified HER2, the drugs that target this protein are ineffective. People that are of African ancestry (AA) are two-to-three times as likely to be diagnosed with basal-like TNBC than people of European ancestry, which is a major disparity and contributes to a significantly poor prognosis. Given that genetic factors have been identified which portend poor outcomes in AA patients, we hypothesize that AA derived tumor cells have unique susceptibilities which can be exploited for therapeutic benefit. The goal of this R21 project is to refine metastasis models systems derived from people of AA as they are currently lacking in abundance and determine novel therapeutic options that may best benefit them. The proposal will (1) develop trackable metastasis models from AA TNBC patient-derived xenografts, (2) define their organ tropism, (3) genomically characterize them at the single-cell level, and (4) identify and test therapeutics which may be beneficial in addition to standard of care chemotherapeutics. The study is innovative through its multifaceted approach and significant as it will directly address a major disparity and provide options for expanded testing of therapeutics that could be utilized in the clinic immediately. The expected outcome of these efforts is that we will develop model systems that can be shared with the broader research community and identify genomic features that are activated in metastases and can be targeted. Achieving these goals will have a positive impact on disparities research and breast cancer treatment.