A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-Derived Human Breast Cancer Xenograft Models

Abstract

Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of SCID/Beige and NOD/SCID/IL2γ-receptor null (NSG) mice, under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were “triple-negative” (ER-PR-HER2+) (n=19). However, we established lines from three ER-PR-HER2+ tumors, one ER+PR-HER2−, one ER+PR+HER2− and one “triple-positive” (ER+PR+HER2+) tumor. Serially passaged xenografts show biological consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including two ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis.

Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution

“…Furthermore, polyclonal sub-structure may emerge even in xenografts that have undergone a modest population bottleneck on initial engraftment. These dynamic processes are not evident from histopathological or imaging characteristics, which remain broadly stable, consistent with previous reports 8,9,23 .…”

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

“…The dose of docetaxel was adjusted (higher dose, 33 mg/kg compared with 20 mg/kg) to treat animals harboring the BCM-4664 xenografts due to its chemoresistance at conventional doses, as previously published (32). Patient's characteristics from the PDX models used have been previously reported (32) and summarized in Table 1. The L-NMMA dose used in these studies is comparable with that previously published and now in clinical trials (clinicatrials.gov NCT02834403), where the hypertensive effect of L-NMMA was reversed with the addition of amlodipine (16,33,34).…”

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“…We assessed the transcriptomic relatedness of the immunocompetent mouse allograft models to a published panel of 25 human breast cancer PDXs [38]. After normalization and batch effect removal, unsupervised hierarchical clustering of the merged datasets showed that mouse model cluster 1 (predominantly M6 and MET1) clustered in the same arm of the dendrogram as the human PDXs while mouse cluster 2 and cluster 3 were distinct (Figure 7).…”

“…The IFNγ score for each sample was defined as the sum of the expression of all the genes on the list. Mouse tumor transcriptomes were then compared with the transcriptomes from a published set of human breast cancer patient-derived xenografts [38]. Among the 21201 mouse genes, 15807 have human homologs.…”