更好地理解产生肿瘤异质性的机制将有助于更好地针对当前的治疗方法，确定潜在的耐药机制，并为治疗提供新的途径。我们先前展示了，在携带有条件致癌等位基因的基因改造小鼠模型中，乳腺肿瘤组织类型的变异取决于等位基因的组合、靶向细胞类型和有些情况下的生殖史。这表明肿瘤异质性不是一个纯粹的随机过程；相反，信号通路的差异激活导致肿瘤组织类型的可重复差异。我们将NOTCH信号通路提出为其中一个此类通路。在这里，我们将有条件敲除Notch1或Notch2等位基因与已建立的小鼠乳腺肿瘤模型进行交叉。Notch1/2的敲除对肿瘤特异性存活没有影响；然而，Notch等位基因的丧失导致原位癌与鳞癌的混合型（ASQCs）呈剂量依赖性增加。ASQCs和腺肌上皮瘤（AMEs）还显示了PI3K/AKT信号的显著增加，而与Notch的状态无关。因此，NOTCH通路是ASQC表型的抑制剂，而增强的PI3K/AKT信号与ASQC和AME肿瘤相关。我们提出了一个模型，其中PI3K/AKT和NOTCH信号相互作用决定小鼠乳腺肿瘤的组织类型。

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.