Breast Cancer PDX Model WHIM2

Technical Information
Published in Cell Reports, WHIM2 is a highly characterized, triple negative (HER2-, ER-, PR-) PDX model of breast cancer. Derived from the primary tumor, this line possesses a S166S insertion in p53. WHIM2 and WHIM5 are derived from the same patient.

Technical Data

Whole Genome Sequenced
No
RNA Sequence
Yes

Tumor Information

Availability
Available
Tumor Site
Primary: Breast
Patient Number
2

Patient Demographics

Age at Diagnosis
44
Patient Race
African American
Family History
None

PAM50 Subtype

PAM50 Originating Tumor
Basal
PAM50 Early Passage
Basal
PAM50 Late Passage
Basal

Genotype/Mutations

ER Status
Negative
PR Status
Negative
HER2 Status
Negative
p53 Genotype
S166S insertion
PIK3CA Genotype
WT
ESR1 Genotype
WT
Phosphoprotein Highest Rank
p90RSK_pT359

Pathology

Specimen Type
Surgical specimen, brain--posterior fossa; surgery core primary
Clinical Stage, Diagnosis
3B
Pathological Stage
3A
Sample Stage
4
Pathology
Ductal; Lobular
Tumor Grade
3
Metastatic Site List
Brain; Bone; Nodes
Systemic Treatments
Grafted sample for WHIM2; Neoadj. DD doxorubicin, Cyclophosphomide, followed by paclitaxel; Adj. chest wall radiation, Tamoxifen; Brain met; Grafted sample for WHIM5
Overall Survival (months)
11

PAM50 Subtype Expression

PAM50 Subtype Microarray
Breast Cancer PDX Model WHIM2 - PAM50 Subtype Microarray
Microarray showing PAM50 subtype. Unsupervised hierarchical clustering of samples using all genes of the microarrays except the stromal-related genes. The colors of the array tree and the squares below the tree denote the subtype call of each sample. Red, basal-like; pink, HER2-enriched; dark blue, lumenal A; light blue, lumenal B; yellow, Claudin-low. Below the array tree and the subtype identification row, the heatmap of the 50 PAM50 genes as well as selected tight-junction-related genes (E-cadherin [CDH1], claudin 3 [CLDN3], CLDN4, and CLDN7) are shown. The stromal-related genes were identified after a two-class paired SAM was performed with an FDR of 0% between 18 paired progenitor human tumors and xenografts.
PAM50 Microarray Validation
Breast Cancer PDX Model WHIM2 - PAM50 Microarray Validation
Validation of PAM50 microarray. Coclustering of 250 human breast samples representing all the PAM50 intrinsic subtypes and 22 HIM models using the 50 PAM50 genes. Gene expression data of all samples has been obtained using 244K Agilent microarrays.
Claudin Low Signature
Breast Cancer PDX Model WHIM2 - Claudin Low Signature
Microarray of 807 genes that make up the Claudin-low signature. On the right, the expression of each gene (up- or downregulated) of the Claudin-low signature is shown. The two Claudin-low samples (WHIM12 and WHIM17) are identified below the array tree.

ER, HER2 and PR Expression

ER and HER2 Western Blots
Breast Cancer PDX Model WHIM2 - ER and HER2 Western Blots
ER and HER2 protein expression. Tumor lysates from ER-positive (A) and ER-negative (B) WHIM lines were analyzed by western blot to confirm ER and HER2 status. Lysates from ER-negative WHIM lines were also probed with antibodies against the cytokeratin 5/6 (CK 5/6) and CD44 markers. The MCF7 (ER-positive), SKBR3 (ER-negative, HER2-positive) and MDA-MB-231 (ER-negative, CD44-positive) breast cancer cell lines were included as blotting controls.

Circos Plots & Phosphoprotein Expression

Circos Plots
Breast Cancer PDX Model WHIM2 - Circos Plots
Circos Plots and Variant Allele Frequency Plots. Overall the Circos plots show closely matched SV and CNV in the tumor of origin and the paired WHIM line. To compare differences in mutant allele frequency between the originating tumor and the PDX counterpart, the read counts for each mutant and wild-type allele were expressed as a percentage of all reads at that position and analyzed by scatter plot and simple correlation coefficient. These show considerably more variation in the human to PDX comparisons but variant allele frequencies are, nonetheless, often preserved.
Phosphoprotein Expression
Breast Cancer PDX Model WHIM2 - Phosphoprotein Expression
Phosphoprotein expression by RPPA. The RPPA data for WHIM samples and 386 TCGA samples were combined after standardizing the data for each marker (i.e., subtracting the mean and then divided by the standard deviation) in the separate data sets. The combined samples were hierarchically clustered using a Pearson correlation based distance matrix ((1-rho)/2, where rho is the Pearson correlation matrix) and the “ward” linkage based on Ward’s minimum variance. In every case the samples from each WHIM line clustered adjacently, including the two double PDX model isolations (WHIM2 and WHIM5, WHIM20 and WHIM23). This demonstrates that intra-PDX heterogeneity was considerably less than the inter-tumoral heterogeneity in a large RPPA data set and was relatively stable over time and passage.
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