The Premalignant Stromal Niche Alters Epithelial Homeostasis in BRCA1-mutant Breast Tumorigenesis

It is now generally accepted that the notion of malignancy extends beyond the genetic and/or epigenetic changes that create a cancerous cell. A rapidly expanding body of literature has exposed the crucial roles of stromal cellular components (e.g., mesenchymal stromal cells (MSCs), endothelial cells, immune cells, and cancer-associated fibroblasts (CAFs)) in establishing the necessary milieu for both tumorigenesis and metastasis. While researchers are making significant strides in understanding the complex cellular and signaling relationships that define this “ecosystem”, more work needs to be done to identify potential therapeutic targets lurking in the tumor microenvironment (1). To this end, a compelling study by Nee et al. uses single-cell RNA sequencing analysis to reveal the presence of altered epithelial homeostasis with expansion of basal-luminal intermediate progenitor cells in breast tissue from germline BRCA1^+/mut carriers (2). The authors report that mutant stromal cells demonstrate elevated expression of proproliferative paracrine signals, with pre-CAFs generating protumorigenic factors such as matrix metalloproteinase 3 (MMP3). The findings presented by Nee et al. further reinforce the importance of understanding stromal-tumor cell interactions and their relevance to clinical oncology.

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