Characterization of human breast cancer xenografts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Ritchie Matthew
PROVIDER: S-ECPF-GEOD-28570 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:A bank of human breast tumor xenografts was established by serial passage of primary breast tumor fragments in the cleared mammary fat pads of immuno-compromised NOD-SCID-IL2Rgammac–/– mice. The 15 expression profiles from five different tumors were classified using the ClaNC method [1]. The training data set consisted of 94 samples from Herschkowitz et al. [2]; class labels were based on tumor subtype (Basal-like, Luminal A, Luminal B, Claudin-low, HER2+/ER- and Normal breast-like). [1] Dabney AR (2005) Classification of microarrays to nearest centroids. Bioinformatics 21:4148-4154. [2] Herschkowitz JI, et al. (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8:R76.
2011-07-07 | GSE28570 | GEO
Project description:A bank of human breast tumor xenografts was established by serial passage of primary breast tumor fragments in the cleared mammary fat pads of immuno-compromised NOD-SCID-IL2Rgammac–/– mice. The 15 expression profiles from five different tumors were classified using the ClaNC method [1]. The training data set consisted of 94 samples from Herschkowitz et al. [2]; class labels were based on tumor subtype (Basal-like, Luminal A, Luminal B, Claudin-low, HER2+/ER- and Normal breast-like). [1] Dabney AR (2005) Classification of microarrays to nearest centroids. Bioinformatics 21:4148-4154. [2] Herschkowitz JI, et al. (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8:R76. Total RNA obtained from xenograft tumors from 5 different patients have been profiled in triplicate on the Illumina HT-12 BeadChip platform.
2011-07-07 | E-GEOD-28570 | biostudies-arrayexpress
Project description:The application of patient-derived xenografts (PDX) in drug screening and testing is a costly and time-consuming endeavor. While cell lines permit extensive mechanistic studies, many human breast cancer cell lines lack patient characteristics and clinical treatment information. Establishing cell lines that retain patient's genetic and drug response information would enable greater drug screening and mechanistic studies. Therefore, we utilized breast cancer PDX from the Mayo Breast Cancer Genome Guided Therapy Study (BEAUTY) to establish two immortalized, genomically unique breast cancer cell lines. Through extensive genetic and therapeutic testing, the cell lines were found to retain the same clinical subtype, major somatic alterations, and drug response phenotypes as their corresponding PDX and patient tumor. Our findings demonstrate PDX can be utilized to develop immortalized breast cancer cell lines and provide a valuable tool for understanding the molecular mechanism of drug resistance and exploring novel treatment strategies.
| S-EPMC8213738 | biostudies-literature
Project description: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 (~23% 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 unique 25 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 phenotypic stability across multiple transplant generations at the histological, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses. 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. The study was designed to determine how stable patient-derived xenografts are across multiple transplant generations in mice, and to determine how closely xenografts established with pre-treatment samples cluster with xenografts established with post-treatment samples. Overall, pre-treatment and post-treatment samples derived from the same patient cluster together, and multiple transplant generations of xenografts derived from an individual patient cluster together.
| S-ECPF-GEOD-46106 | biostudies-other
Project description: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 (~23% 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 unique 25 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 phenotypic stability across multiple transplant generations at the histological, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses. 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.
2013-05-30 | GSE46106 | GEO
Project description:Pharmacological targeting of breast cancer stem cells (CSCs) is highly promising for the treatment of breast cancer, as the small population of CSCs appears responsible for tumor initiation and progression and also for resistance to conventional treatment. Here we report that the novel phosphosulindac (OXT-328, PS) selectively and effectively eliminates breast CSCs both in vitro and in vivo. PS reduced cell proliferation and induced apoptosis in various breast CSCs. Breast CSCs are resistant to conventional cancer drugs but are sensitive to PS. Long-term treatment of mixtures of cultured breast CSCs and breast cancer cells with PS preferentially eliminated the CSCs. PS impaired the ability of CSCs to form mammospheres and markedly suppressed the expression of CSC-related genes. More importantly, PS prevented by half (p = .06) the formation of tumors initiated by CSCs in immunodeficient mice, and inhibited by 83% (p < .05) the growth of already formed breast cancer xenografts, reducing the proportion of CSCs in them. PS suppressed the Wnt/β-catenin pathway by stimulating the degradation of β-catenin and its relocalization to the cell membrane and also blocked the epithelial-mesenchymal transition and the generation of breast CSCs. These results indicate that PS has a strong inhibitory effect against breast cancer, acting, at least in part, by targeting CSCs through a signaling mechanism involving Wnt signaling.
| S-EPMC3621090 | biostudies-literature
Project description:Beta(1) integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of beta(1) integrin signaling. We previously showed that beta(1) integrin inhibitory antibodies (e.g., AIIB2) enhance apoptosis and decrease growth in human breast cancer cells in three-dimensional laminin-rich extracellular matrix (lrECM) cultures and in vivo. Here, we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used three-dimensional lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in three-dimensional lrECM. Colonies were assayed for apoptosis and beta(1) integrin/Akt signaling pathways were evaluated using Western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in three-dimensional lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down-regulating Akt in breast cancer colonies in three-dimensional lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared with either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We previously showed that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.
| S-EPMC3719863 | biostudies-literature
Project description:To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.
| S-EPMC3881975 | biostudies-literature
Project description:A major problem in the therapeutic management of cancer is the growth of metastases in distant organs, but the genes orchestrating the process need to be identified for the rational design of new treatment. Here, we provide decisive experimental evidence demonstrating the causal involvement of a specific gene, osteopontin (OPN), in the pathogenesis of metastasis by human breast cancer cells and implicating some of its probable partners. Stable long-term depletion, or up-regulation, of OPN gene expression in a matched, isogenic pair of human breast cancer cell lines of differing metastatic proficiency reproducibly changed their ability to colonize distant organs. OPN down-regulation was achieved by transduction of the metastatic line with a DNA construct encoding a small hairpin RNA in a vector labeled with red fluorescent protein and resulted in a marked reduction of metastatic load (P < 0.01). Up-regulation of OPN in the negligibly metastatic line, with a green fluorescent protein-marked retroviral vector containing OPN cDNA driven by a strong promoter, resulted in heavy colonization of the lungs and lymph nodes (P < 0.005). The reciprocal changes in behavior of these matched cell lines cross-corroborate each other. Concomitant changes were seen in the expression of other metastasis-related genes in both modulated lines. The data indicate that therapeutic targeting of tumor OPN molecules could reset metastatically relevant gene networks, resulting in clinical benefit.
| S-EPMC1934534 | biostudies-literature
Project description:BackgroundTumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model.Materials and methods5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67-staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU).ResultsHBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model.ConclusionDespite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the number and area of metastatic lesions in the triple negative model as well as a significant reduction in the EMT markers N-cadherin, Axl and density of collagen type I.
| S-EPMC5568407 | biostudies-literature