PDX Breast Cancer Model WHIM18

Technical Information
Published in Cell Reports, WHIM18 is a highly characterized, HER2-, ER+, PR+ PDX model of breast cancer. Derived from a skin metastasis, this line possesses an ESR1-YAP1 fusion, and an E545K mutation in PIK3CA. This line grows independently of estradiol. Whole genome sequencing data is available for this line.

Technical Data

Estradiol Response
Independent
Whole Genome Sequenced
Yes
RNA Sequence
Yes

Tumor Information

Availability
Available
Tumor Site
Metastasis: Skin
Patient Number
18

Patient Demographics

Age at Diagnosis
57
Patient Race
African American
Family History
None

PAM50 Subtype

PAM50 Originating Tumor
Luminal A
PAM50 Early Passage
Luminal B
PAM50 Late Passage
Luminal B

Genotype/Mutations

ER Status
Positive
PR Status
Positive
HER2 Status
Negative
p53 Genotype
WT
PIK3CA Genotype
E545K
ESR1 Genotype
ESR1 YAP1
Phosphoprotein Highest Rank
ER-alpha_pS118

Pathology

Specimen Type
Punch -- primary
Clinical Stage, Diagnosis
4
Pathological Stage
4
Sample Stage
4
Pathology
Ductal
Tumor Grade
2
Metastatic Site List
Brain; Bone; Nodes; Lung; Liver
Systemic Treatments
Letrozole; exemestane; fulvestrant; Grafted sample for WHIM18; capecitabine; paclitaxel, bevacizumab; Tamoxifen; Radiation to the calvarium completed; Doxil
Overall Survival (months)
31

PAM50 Subtype Expression

PAM50 Subtype Microarray
PDX Breast Cancer Model WHIM18 - 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
PDX Breast Cancer Model WHIM18 - 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
PDX Breast Cancer Model WHIM18 - 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
PDX Breast Cancer Model WHIM18 - 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
PDX Breast Cancer Model WHIM18 - Circos Plots
Circos Plots and Variant Allele Frequency Plots. The circos plots for show the closely matched SVs and CNVs 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 scatterplot and simple correlation coefficient. WHIM18 has a high correlation coefficient (0.84) in both the coding region (yellow) and noncoding region (blue). The VAF stability was maintained across all six SMG mutations.
Phosphoprotein Expression
PDX Breast Cancer Model WHIM18 - 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.

Estradiol Response & ESR1 Expression

Estradiol Response
PDX Breast Cancer Model WHIM18 - Estradiol Response
Estradiol Dependency and Tumor Doubling Times. Figure 1: Tumor cells were subcutaneously injected into ovariectomized NOD/SCID mice and then immediately treated with 17ß-estradiol pellets or observed.

Figure 2: Fragments of WHIM18 tumor tissue were subcutaneously engrafted into female CB.17 SCID mice. Tumor-bearing mice were treated in the presence or absence of fulvestrant when tumor size reached 300 mm3. All data were analyzed in SAS using the PROC MIXED function.
ESR1 Western Blot
PDX Breast Cancer Model WHIM18 - ESR1 Western Blot
Western blot for the expression of endogenous and exogenous ESR1. Western blot for the expression of endogenous and exogenous ESR1 using an N-terminal antibody and two direct ESR1 downstream targets (progesterone receptor [PR-A and PR-B] and TFF1) with an actin loading control. Due to the substantially lower basal TFF1 expression in T47D cells compared with MCF7 cells, the T47D TFF1 blot was intentionally exposed for a longer time for visualization.
Protocols & Documents
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