NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity

SIMPLE SUMMARY: Effective personalised cancer therapy depends on an understanding of the fundamental biological differences between tumours. Such differences may include the activation or suppression of molecular pathways involved in the development and regulation of the normal cells that give rise to the cancer of interest. One such candidate pathway in mammary/breast cancer is NOTCH signalling. In a mouse model of mammary cancer, which normally develops four different histological tumour types upon knockout of the Pten and p53 tumour suppressor genes in the mammary gland, the additional knockout of the Notch1 or Notch2 genes did not alter the kinetics of tumour onset but did significantly change the relative proportions of different tumour types. This was accompanied by changes in PI3K/AKT signalling. We suggest PI3K/AKT and NOTCH signalling interact to determine mouse mammary tumour histotype. ABSTRACT: A better understanding of the mechanisms generating tumour heterogeneity will allow better targeting of current therapies, identify potential resistance mechanisms and highlight new approaches for therapy. We have previously shown that in genetically modified mouse models carrying conditional oncogenic alleles, mammary tumour histotype varies depending on the combination of alleles, the cell type to which they are targeted and, in some cases, reproductive history. This suggests that tumour heterogeneity is not a purely stochastic process; rather, differential activation of signalling pathways leads to reproducible differences in tumour histotype. We propose the NOTCH signalling pathway as one such pathway. Here, we have crossed conditional knockout Notch1 or Notch2 alleles into an established mouse mammary tumour model. Notch1/2 deletion had no effect on tumour-specific survival; however, loss of Notch alleles resulted in a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs). ASQCs and adenomyoepitheliomas (AMEs) also demonstrated a significant increase in AKT signalling independent of Notch status. Therefore, the NOTCH pathway is a suppressor of the ASQC phenotype, while increased PI3K/AKT signalling is associated with ASQC and AME tumours. We propose a model in which PI3K/AKT and NOTCH signalling act interact to determine mouse mammary tumour histotype.