Breast cancer is the most commonly diagnosed cancer in female worldwide. Among three clinical categorized breast cancer groups, the oestrogen receptor-positive (ER+)/luminal group has the highest mutation frequency of PIK3CA, occurring in 45% of cases. In contrast, only around 9% of basal-like tumours carry PIK3CA mutations1. Despite a number of studies on the clinical relevance of these mutations, the molecular mechanisms underlying PIK3CA oncogenicity are not well understood and the cancer cell-of-origin remains to be determined.
In this study, we used the Cre/LoxP system to generate mouse models with mammary epithelial-specific expression of Pik3caH1047R mutation2 under the control of different Cre driver genes including the mouse mammary tumour virus promoter (MMTV) and luminal specific promoters. H1047R is the most common hotspot for activating PIK3CA mutations. For the model driven by the mouse mammary tumour virus promoter (MMTV-cre), we confirmed constitutive activation of the PI3K pathway in Pik3caH1047R mutated mammary glands and tumours. Pik3caH1047R mutated tumours were found mostly ER+, moderately proliferative and organised into glandular structures expressing epithelial cytokeratins. However, with the simultaneous heterozygous deletion of Trp53, the tumours became highly proliferative and mesenchymal-like, lacking in epithelial characteristics. Interestingly, Tspan8 expression was increased only in the basal compartment of Pik3caH1047R mutated mammary glands and tumours, but not in tumours with concurrent heterozygous loss of TP53. Single-cell RNA sequencing data confirmed that Tspan8 was elevated in basal epithelial cells in Pik3caH1047R preneoplastic mammary glands at the transcriptomic level. Current work aims at investigating cells-of-origin of cancer and the underlying signalling pathways. Our data suggest that conditional activation of Pik3caH1047R gives rise to ER+ breast tumours and leads to Tspan8+ cell expansion during tumourigenesis, which might be repressed by loss of TP53.