Low‐grade and high‐grade mammary carcinomas in WAP‐T transgenic mice are independent entities distinguished by Met expression

Abstract

Mammary carcinomas developing in SV40 transgenic WAP-T mice arise in two distinct histological phenotypes: as differentiated low-grade and undifferentiated high-grade tumors. We integrated different types of information such as histological grading, analysis of aCGH-based gene copy number and gene expression profiling to provide a comprehensive molecular description of mammary tumors in WAP-T mice. Applying a novel procedure for the correlation of gene copy number with gene expression on a global scale, we observed in tumor samples a global coherence between genotype and transcription. This coherence can be interpreted as a matched transcriptional regulation inherited from the cells of tumor origin and determined by the activity of cancer driver genes. Despite common recurrent genomic aberrations, e.g. gain of chr. 15 in most WAP-T tumors, loss of chr. 19 frequently occurs only in low-grade tumors. These tumors show features of ''basal-like'' epithelial differentiation, particularly expression of keratin 14. The high-grade tumors are clearly separated from the low-grade tumors by strong expression of the Met gene and by coexpression of epithelial (e.g. keratin 18) and mesenchymal (e.g. vimentin) markers. In high-grade tumors, the expression of the nonmutated Met protein is associated with Met-locus amplification and Met activity. The role of Met as a cancer driver gene is supported by the contribution of active Met signaling to motility and growth of mammary tumor-derived cells. Finally, we discuss the independent origin of low-and high-grade tumors from distinct cells of tumor origin, possibly luminal progenitors, distinguished by Met gene expression and Met signaling.Mouse models provide important tools for gaining insight into the biology of breast cancer (BC) and the relationship between histopathology and molecular profiles of cancer subtypes. 1,2 They narrow down the complexity of the disease and allow defining the influence of specific individual molecular factors and pathways on BC development and progression-information that is difficult to obtain from retrospective analyses of human tumor samples. Mammary epithelial

Chemotherapy of WAP‐T mouse mammary carcinomas aggravates tumor phenotype and enhances tumor cell dissemination

“…Initiated WAP-T mice develop mammary carcinomas, which could be cross-species validated with corresponding human tumors. 11,12 From an undifferentiated WAP-T tumor (T1-H22 9,13 ), the authors established a mammary cancer cell line (G-2).…”

Aberrant Proliferation of Differentiating Alveolar Cells Induces Hyperplasia in Resting Mammary Glands of SV40-TAg Transgenic Mice

“…Furthermore, they were described as potential targets of activated oncogenes in transgenic mice giving rise to mammary gland tumors (22, 23). High grade tumors in WAP-T1 mice showed significant expression of CK6 as assayed by gene expression analysis (26). Thus, we asked whether TAg targets CK6a positive cells in resting uniparous WAP-T1 glands.…”

“…This raises the question whether oncogenic activity of TAg in WAP-T1 mice at the early stage of hyperplasia randomly targets epithelial cells or promotes selection of a distinct cell type. Gene expression analysis of advanced WAP-T1 tumors identified at least two different tumor entities, which completely differ in marker expression: (i) low grade tumors, exhibiting a basal-like and morphologically differentiated phenotype with loss of chromosomes 2 and 19 and (ii) high grade tumors marked by strong expression of the Met gene and by co-expression of keratin 8/18, keratin 6, and the mesenchymal marker vimentin (26). But, a heterogeneous cell composition of advanced tumors does not necessarily contradict the idea that TAg selects for a distinct epithelial cell type.…”

Cancer immunotherapy: weak beats strong

“…Using the well characterized and cross-species validated BALB/c mouse based WAP-T models for triple-negative breast cancer [3,4], we assessed the role of tumor antigen T-cell immunogenicity in PD1/PD-L1 immune checkpoint blockade therapy [5]. We compared the response to anti-PD1/PD-L1 antibody therapy in two different lines of tumor mice (WAP-T and WAP-T NP mice, respectively) immunologically differing only in the expression of a single T-cell epitope in their major tumor antigen: WAP-T and WAP-T NP mice contain both as transgene the SV40 early gene region under control of the whey acidic protein (WAP) promoter, which upon induction codes for SV40 early proteins, with T-antigen being the major tumor antigen.…”