Abstract
ABSTRACTUnderstanding the mechanisms underlying tumour heterogeneity is key to the development of treatments that can target specific tumour subtypes. We have previously targeted CRE recombinase-dependent conditional deletion of the tumour suppressor genes Brca1, Brca2, p53 (also known as Trp53) and/or Pten to basal or luminal oestrogen receptor-negative (ER−) cells of the mouse mammary epithelium. We demonstrated that both the cell-of-origin and the tumour-initiating genetic lesions cooperate to influence mammary tumour phenotype. Here, we use a CRE-activated HER2 orthologue to specifically target HER2/ERBB2 oncogenic activity to basal or luminal ER− mammary epithelial cells and perform a detailed analysis of the tumours that develop. We find that, in contrast to our previous studies, basal epithelial cells are less sensitive to transformation by the activated NeuKI allele, with mammary epithelial tumour formation largely confined to luminal ER− cells. Histologically, most tumours that developed were classified as either adenocarcinomas of no special type or as metaplastic adenosquamous tumours. The former were typically characterized by amplification of the NeuNT/Erbb2 locus; in contrast, tumours displaying squamous metaplasia were enriched in animals that had been through at least one pregnancy and typically had lower levels of NeuNT/Erbb2 locus amplification but had activated canonical WNT signalling. Squamous changes in these tumours were associated with activation of the epidermal differentiation cluster. Thus, in this model of HER2 breast cancer, cell-of-origin, reproductive history, NeuNT/Erbb2 locus amplification and the activation of specific branches of the WNT signalling pathway all interact to drive inter-tumour heterogeneity.
Highlights
The ERBB2/HER2 receptor tyrosine kinase is amplified and overexpressed in 20-30% of human breast cancers, leading to an aggressive form of the disease (Andrulis et al, 1998)
Comparison of relative expression levels of endogenous Erbb2 in each mammary epithelial subpopulation showed that endogenous Erbb2 was expressed at lower levels in the transgenic/knock-in lines than in the wild-type cells in three of the four populations, the exception being the luminal ER+ cells, in which it was higher in the transgenic/knock-in lines than in the wild-type cells (Fig. S1C)
These differences may result from a combination of the design/expression of the genetic constructs in the transgenic/ knock-in lines, as well as the difference in background strains
Summary
The ERBB2/HER2 receptor tyrosine kinase (a member of the epidermal growth factor receptor family) is amplified and overexpressed in 20-30% of human breast cancers, leading to an aggressive form of the disease (Andrulis et al, 1998). In previous studies of mammary tumour origin, we used genetically engineered mouse models in which CRE recombinasedependent conditional deletion of the tumour suppressor genes Brca, Brca, p53 ( known as Trp53) and/or Pten were targeted to basal or luminal ER− cells using the Krt or Blg promoters, respectively. We demonstrated that both the cell-of-origin and the tumour-initiating genetic lesions cooperate to influence the tumour behaviour, with a more diverse range of tumour phenotypes arising from luminal ER− cells but basal-origin tumours having significantly shorter latency (Melchor et al, 2014; Molyneux et al, 2010)
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