NOTCH and AKT Signalling Interact to Drive Mammary Tumour Heterogeneity

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Tumor heterogeneity influences therapeutic strategies and resistance mechanisms.
• Mammary tumor histotype in mouse models depends on oncogenic alleles, cell type, and reproductive history, suggesting non-stochastic origins.
• Signaling pathways play a critical role in determining reproducible differences in tumor histotype.

Purpose of the Study:

• To investigate the role of the NOTCH signaling pathway in regulating mouse mammary tumor heterogeneity.
• To determine the effect of NOTCH1 and NOTCH2 deletion on mammary tumor development and histotype.
• To explore the relationship between NOTCH signaling, PI3K/AKT signaling, and the development of metaplastic adenosquamous carcinomas (ASQCs) and adenomyoepitheliomas (AMEs).

Main Methods:

• Utilized genetically modified mouse models with conditional knockout alleles for Notch1 or Notch2.
• Crossed these conditional knockout alleles into an established mouse mammary tumor model.
• Analyzed tumor histotype, tumor-specific survival, and AKT signaling activation in the presence and absence of NOTCH alleles.

Main Results:

• Deletion of Notch1/2 alleles did not impact tumor-specific survival.
• Loss of NOTCH alleles led to a dose-dependent increase in metaplastic adenosquamous carcinomas (ASQCs).
• ASQCs and adenomyoepitheliomas (AMEs) showed increased AKT signaling, irrespective of NOTCH status.

Conclusions:

• The NOTCH pathway acts as a suppressor of the ASQC phenotype in mouse mammary tumors.
• Increased PI3K/AKT signaling is significantly associated with ASQC and AME tumor development.
• A model is proposed where PI3K/AKT and NOTCH signaling pathways interact to determine mouse mammary tumor histotype.