Unknown,Transcriptomics,Genomics,Proteomics

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A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-derived Human Breast Cancer Xenografts

ABSTRACT: Translational 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. In an effort to overcome these limitations, we propagated a cohort of human breast tumors grown in the mammary fat pad of SCID/Beige and NOD/SCID/IL2?-receptor null (NSG) two relatively new immunocompromised mouse models, under a series of transplant conditions. Both models yielded stably transplantable xenografts relatively high rates compared with previously available immunocompromised mice. Xenograft lines were established directly from breast cancer patient samples, without intervening culture in vitro, using the epithelium-free mammary fat pad as the transplantation site. Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 35 stably transplantable xenograft lines representing 27 patients were established, using pre-treatment, mid-treatment, and/or post-treatment samples. Most patients yielding xenografts were “triple-negative” (ER-PR-HER2-) (n=21). However, we were able to establish lines from three ER-PR-HER2+ patients, one ER+PR-HER2-, one ER+PR+HER2- and one “triple-positive” (ER+PR+HER2+) patient. Serially passaged xenografts show biological consistency with the tumor of origin at the histopathology level, and remarkable stability across multiple transplant generations at the genomic, transcriptomic, and proteomic levels. Of the 27 patients represented, xenografts derived from 13 patients showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource, and should prove useful for preclinical evaluation of experimental therapeutics. reference x sample

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Perou

PROVIDER: E-GEOD-34412 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models.

Zhang Xiaomei X Claerhout Sofie S Prat Aleix A Dobrolecki Lacey E LE Petrovic Ivana I Lai Qing Q Landis Melissa D MD Wiechmann Lisa L Schiff Rachel R Giuliano Mario M Wong Helen H Fuqua Suzanne W SW Contreras Alejandro A Gutierrez Carolina C Huang Jian J Mao Sufeng S Pavlick Anne C AC Froehlich Amber M AM Wu Meng-Fen MF Tsimelzon Anna A Hilsenbeck Susan G SG Chen Edward S ES Zuloaga Pavel P Shaw Chad A CA Rimawi Mothaffar F MF Perou Charles M CM Mills Gordon B GB Chang Jenny C JC Lewis Michael T MT

Cancer research 20130604 15

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 severe combined immunodeficient (SCID)/Beige and nonobese diabetic (NOD)/SCID/IL-2γ-receptor null (NSG) mice under a series of transplant conditions. Both models yielded stably ...[more]

PMID: 23737486

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Project description:The number of relevant and well-characterized cell lines and xenograft models for studying human breast cancer are few, and may represent a limitation for this field of research. With the aim of developing new breast cancer model systems for in vivo studies of hormone dependent and independent tumor growth, progression and invasion, and for in vivo experimental therapy studies, we collected primary mammary tumor specimens from patients, and implanted them in immunodeficient mice. Primary tumor tissue from 29 patients with breast cancer was implanted subcutaneously with matrigel in SCID mice, in the presence of continuous release of estradiol. The tumors were transferred into new animals when reaching a diameter of 15mm and engrafted tumors were harvested for morphological and molecular characterization from passage six. Further, gene expression profiling was performed using Agilent Human Whole Genome Oligo Microarrays, as well as DNA copy number analysis using Agilent Human Genome CGH 244K Microarrays. Of the 30 primary tumors implanted into mice (including two implants from the same patient), two gave rise to viable tumors beyond passage ten. One showed high expression levels of estrogen receptor-alpha protein (ER) while the other was negative. Histopathological evaluation of xenograft tumors was carried out at passage 10-12; both xenografts maintained the morphological characteristics of the original tumors (classified as invasive grade III ductal carcinomas). The genomic profile of the ER-positive xenograft tumor resembled the profile of the primary tumor, while the profile obtained from the ER-negative parental tumor was different from the xenograft. However, the ER-negative parental tumor and xenograft clustered on the same branch using unsupervised hierarchical clustering analysis on RNA microarray expression data of "intrinsic genes". A significant variation was observed in the expression of extracellular matrix (ECM)-related genes, which were found downregulated in the engrafted tumors compared to the primary tumor. By IHC and qRT-PCR we found that the downregulation of stroma-related genes was compensated by the overexpression of such molecules by the mouse host tissue. The two established breast cancer xenograft models showed different histopathological characteristics and profound diversity in gene expression patterns that in part can be associated to their ER status and here described as basal-like and luminal-like phenotype, respectively. These two new breast cancer xenografts represent useful preclinical tools for developing and testing of new therapies and improving our knowledge on breast cancer biology. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc.

Dataset Information

A Renewable Tissue Resource of Phenotypically Stable, Biologically and Ethnically Diverse, Patient-derived Human Breast Cancer Xenografts

Publications

A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models.

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