A genetic mosaic mouse model illuminates the pre-malignant progression of basal-like breast cancer

Abstract

Basal-like breast cancer is an aggressive breast cancer subtype, often characterized by a deficiency in BRCA1 function and concomitant loss of p53. While conventional mouse models enable the investigation of its malignant stages, one that reveals its initiation and pre-malignant progression is lacking. Here, we leveraged a mouse genetic system known as Mosaic Analysis with Double Markers (MADM) to generate rare GFP-labeled Brca1, p53-deficient cells alongside RFP+ wildtype sibling cells in the mammary gland. The mosaicism resembles the sporadic initiation of human cancer and enables spatially resolved analysis of mutant cells in comparison to paired wildtype sibling cells. Mammary tumors arising in the model show transcriptomic and genomic characteristics similar to human basal-like breast cancer. Analysis of GFP+ mutant cells at interval time points before malignancy revealed a stepwise progression of lesions from focal expansion to hyper-alveolarization and then to micro-invasion. These stereotyped morphologies indicate the pre-malignant stage irrespective of the time point at which it is observed. Paired analysis of GFP-RFP siblings during focal expansion suggested that hyper-alveolarized structures originate from ductal rather than alveolar cells, despite their morphological similarities to alveoli. Evidence for luminal-to-basal transition at the pre-malignant stages was restricted to cells that had escaped hyper-alveoli and progressed to micro-invasive lesions. Our MADM-based mouse model presents a useful tool for studying the pre-malignancy of basal-like breast cancer. Summary statementA mouse model recapitulates the process of human basal-like breast tumorigenesis initiated from sporadic Brca1, p53-deficient cells, empowering spatially-resolved analysis of mutant cells during pre-malignant progression.