Stromal cells drive tumorigenesis in BRCA1 mutation carriers

摘要

The initiation of BRCA1-mediated breast cancer is linked to pre-malignant changes in the breast epithelium; however, the effect of BRCA1 mutations on the surrounding stromal cells has not yet been elucidated. Nee et al. now demonstrate that the stromal niche promotes tumorigenesis and epithelial proliferation via paracrine signalling in carriers of the BRCA1 mutation (BRCA1+/mut). Single-cell RNA sequencing (scRNA-seq) of the epithelial and stromal compartments found several features of perturbed differentiation in breast epithelial cells from BRCA1+/mut carriers, including the upregulation of basal hallmark genes in luminal epithelial cells - resulting in an expanded population of basal-luminal intermediate progenitors - and an increased percentage of cells in S phase. Furthermore, the authors observed increased expression of genes encoding protumorigenic and proliferative growth factors in the stromal pericytes and fibroblasts of BRCA1+/mut carriers compared to noncarriers. The scRNA-seq data showed that fibroblasts in BRCA1+/mut carriers possess a similar transcriptional signature to that of cancer-associated fibroblasts (CAFs), which have been linked to tumour progression. The gene encoding MMP3 was one of the top CAF markers elevatedin BRCA1/mut fibroblasts; as this gene has previously been linked to tumorigenesis, the authors investigated whether fibroblast-derived MMP3 is responsible for the altered epithelial differentiation in BRCA1+/mut carriers. Immunofluorescence of BRCA1+/mut breast tissue revealed an increased number of MMP3-positive stromal cells proximal to the epithelium, and a 3D coculture of primary breast fibroblasts and epithelial cells showed that fibroblast-specific overexpression of MMP3 or exogenous MMP3 increased epithelial cell growth, whereas reduced growth was seen using fibroblasts lacking MMP3. A protumorigenic role for MMP3 was further supported by a tumour initiation model in which human fibroblasts were transplanted into immunocompromised mice carrying precancerous human mammary cells; mice receiving MMP3-overexpressing fibroblasts showed increased tumour mass, volume and initiation frequency compared to controls. These findings implicate MMP3 as a potential drug target for the prevention of primary cancers and could inform therapeutic strategies for BRCA1+/mut patients.