NOTCH and AKT signalling interact to drive mammary tumour heterogeneity

Ordonez, Liliana, Tornillo, Giusy, Kendrick, Howard, Hay, Trevor and Smalley, Matthew John ORCID: https://orcid.org/0000-0001-9540-1146 2023. NOTCH and AKT signalling interact to drive mammary tumour heterogeneity. Cancers 15 (17) , 4324. 10.3390/cancers15174324

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	MDPI
ISSN:	2072-6694
Funders:	Cancer Research UK
Date of First Compliant Deposit:	30 August 2023
Date of Acceptance:	26 August 2023
Last Modified:	25 Sep 2023 16:34
URI:	https://orca.cardiff.ac.uk/id/eprint/162098

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