Department of Medicine, University of California, San Francisco, CA 94115, USA.
Department Laboratory Medicine, University of California, San Francisco, CA 94115, USA.
Breast Cancer Res Treat. 2012 Oct;135(3):913-22. doi: 10.1007/s10549-012-2226-y. Epub 2012 Sep 2.
Though xenografts are used extensively for drug development in breast cancer, how well xenografts reflect the breadth of primary breast tumor subtypes has not been well characterized. Moreover, few studies have compared the gene expression of xenograft tumors to the primary tumors from which they were derived. Here we investigate whether the ability of human breast tumors (n = 20) to create xenografts in immune-deficient mice is associated with breast cancer immunohistochemical (IHC) and intrinsic subtype. We also characterize how precisely the gene expression of xenografts reprises that of parent breast tumors, using hierarchical clustering and other correlation-based techniques applied to Agilent 44K gene expression data from 16 samples including four matched primary tumor-xenograft pairs. Of the breast tumors studied, 25 % (5/20) generated xenografts. Receptor and intrinsic subtype were significant predictors of xenograft success, with all (4/4) triple-negative (TN) tumors and no (0/12) HR+Her2- tumors forming xenografts (P = 0.0005). Tumor cell expression of ALDH1, a stem cell marker, trended toward successful engraftment (P = 0.14), though CDK5/6, a basal marker, did not. Though hierarchical clustering across the 500 most variable genes segregated human breast tumors from xenograft tumors, when clustering was performed over the PAM50 gene set the primary tumor-xenograft pairs clustered together, with all IHC subtypes clustered in distinct groups. Greater similarity between primary tumor-xenograft pairs relative to random pairings was confirmed by calculation of the within-pair between-pair scatter ratio (WPBPSR) distribution (P = 0.0269), though there was a shift in the xenografts toward more aggressive features including higher proliferation scores relative to the primary. Triple-negative breast tumors demonstrate superior ability to create xenografts compared to HR+ tumors, which may reflect higher proliferation or relatively stroma-independent growth of this subtype. Xenograft tumors' gene expression faithfully resembles that of their parent tumors, yet also demonstrates a shift toward more aggressive molecular features.
尽管异种移植物在乳腺癌的药物开发中被广泛应用，但异种移植物在多大程度上反映了原发性乳腺癌亚型的广泛性尚未得到很好的描述。此外，很少有研究比较异种移植瘤的基因表达与起源于它们的原发性肿瘤。在这里，我们研究了人类乳腺癌（n=20）在免疫缺陷小鼠中形成异种移植物的能力是否与乳腺癌免疫组织化学（IHC）和固有亚型有关。我们还通过层次聚类和其他基于相关性的技术，利用来自 16 个样本的安捷伦 44K 基因表达数据（包括 4 对匹配的原发性肿瘤-异种移植瘤对），来描述异种移植瘤的基因表达与亲代乳腺癌肿瘤的精确重现程度。在研究的乳腺癌中，25%（5/20）形成了异种移植物。受体和固有亚型是异种移植成功的显著预测因子，所有（4/4）三阴性（TN）肿瘤和没有（0/12）HR+Her2-肿瘤形成异种移植物（P=0.0005）。肿瘤细胞中 ALDH1 的表达，一种干细胞标志物，倾向于成功植入（P=0.14），而基底标志物 CDK5/6 则不然。尽管跨 500 个最具变异性的基因进行层次聚类将人类乳腺癌与异种移植瘤区分开来，但当基于 PAM50 基因集进行聚类时，原发性肿瘤-异种移植瘤对聚类在一起，所有 IHC 亚型都聚类在不同的组中。通过计算配对内-配对间散度比（WPBPSR）分布来确认原发性肿瘤-异种移植瘤对之间的相似性大于随机配对（P=0.0269），尽管相对于原发性肿瘤，异种移植瘤向更具侵袭性的特征（包括更高的增殖评分）发生了转移。与 HR+肿瘤相比，三阴性乳腺癌具有形成异种移植物的卓越能力，这可能反映了该亚型的更高增殖或相对与基质无关的生长。异种移植瘤的基因表达与亲代肿瘤非常相似，但也表现出向更具侵袭性的分子特征的转变。
