Basal-like breast cancer (BLBC) is a particularly aggressive disease, typically occurring in younger women and devastatingly associated with poor prognosis. These cancers lack expression of oestrogen, progesterone and HER2 receptors, and so patients have limited benefit from the hormone and targeted therapies that have revolutionized treatment options in other types of breast cancer. Loss of Trp53 and BRCA1 tumour suppressor genes are common drivers in BLBC, a causality that has been endorsed in mouse models with mammary-specific Brca1/p53 deletion. However, cellular changes elicited by genetic mutations in the early stages of disease progression have been difficult to study. This is a key gap, as it could guide us towards early detection and prevention strategies that would be significant advancements in the clinical management of BLBC.
Addressing this gap, Zeng et al., in this issue of DMM, describe a mouse model in which permanent marking of sporadic naïve mammary cells that lose Tp53 and Brca1 allows the tracking of the subsequent expansion of pre-malignant clones. This is achieved through an inter-chromosomal genetic recombination system in which cells bearing the homozygous mutations are induced and simultaneously, yet exclusively, express a green fluorescent protein. Particularly elegant is the fact that this occurs in actively dividing cells, so sister ‘wild-type’ cells are permanently marked with a red fluorescence protein. This enables direct phenotypical comparison between mutated and sibling wild-type cells within a natural context.
Incorporating whole-tissue imaging techniques at single-cell resolution, the authors used this model to visualize sporadic, GFP-marked mutant cells within overtly normal mammary glands, identifying rare cells with tumour-initiating capacity. By performing time-course analysis, they then tracked the gradual expansion of mutant cells, from premalignant ductal morphological changes to the outgrowth of mutant (but not wild-type) clusters of cells or ‘clones’ and, ultimately, to highly proliferative tumours representative of human BLBC. An interesting facet of the study was the evidence suggesting that the origins of cancer outgrowths was the ductal rather than alveolar lineage in the mammary epithelium, and that partial luminal-to-basal transition was involved during progressive malignant changes. This model provides a resource to elucidate how these changes might be monitored in patients or be therapeutically targeted within a cancer prevention setting. Furthermore, this powerful system of monitoring rare sporadic tumour-initiating events enables the study of early disease and can be applied to many mouse models of cancer.
DMM Research or Resource articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.