PIK3CAH1047R induces multipotency and multi-lineage mammary tumours

Abstract

The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CA(H1047R), one of the most frequent mutations occurring in human breast cancer, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CA(H1047R) in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CA(H1047R) on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CA(H1047R) tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.

Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

“…Other recent studies have demonstrated that basal and luminal cells of the mouse mammary gland can be transformed by mutant PIK3CA H1047R overexpression (28,29). Mutant PIK3CA in basal cells evoked benign tumors, such as adenomyoepithelioma and fibroadenoma, in contrast to the mostly aggressive mammary tumors, including adenosquamous carcinoma and carcinosarcoma, when it was expressed in luminal cells.…”

“…Hi basal cell 1,000 21 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) Intriguingly, human basal-and luminal-derived tumors demonstrate histologically distinct phenotypes when challenged with the same oncogenes, MYC and AKT1. Tumors derived from basal cells are of a higher grade than tumors derived from luminal cells.…”

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

“…7 Further studies will determine whether the potential MYC-induced cell fate switch observed here bears similarities to recent discoveries of oncogene-induced cell fate conversions in lineage restricted subpopulations and whether it contributes to tumor heterogeneity in human breast cancer. 47,48 …”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…The natural history of breast cancer still remains poorly understood, and may differ by cell of origin [114,115], subtype or yet unknown factors. However, a preponderance of evidence now shows that the insoluble proteins comprising the extracellular matrix (ECM) can suppress tumor development and progression, whereas the abnormal ECM in tumors can promote progression of cancers and resistance to treatment.…”