Single-Cell RNA Sequencing Reveals the Cellular Origin and Evolution of Breast Cancer in BRCA1 Mutation Carriers

Abstract

The cell of origin and the development of breast cancer are not fully elucidated in BRCA1 mutation carriers, especially for estrogen receptor (ER)-positive breast cancers. Here, we performed single-cell RNA sequencing on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four BRCA1 mutation carriers and three non-carriers. Whole-exome sequencing was performed on breast tumors from the four BRCA1 mutation carriers; for validation, bulk RNA sequencing was performed on adjacent normal breast tissues from eight additional BRCA1 mutation carriers and fourteen non-carriers. Correlation analyses suggested that breast cancers in BRCA1 mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in BRCA1 mutation carriers compared with non-carriers. These observations were further validated by the bulk RNA sequencing data from additional BRCA1 mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ER neg ) in BRCA1 mutation carriers might be luminal progenitor cells. The expression of TP53 and BRCA1 was decreased in luminal progenitor cells from normal breast tissue in BRCA1 mutation carriers, which might trigger the basal/mesenchymal transition of luminal progenitors and might result in basal-like tumor development. Furthermore, ER high luminal tumors might originate from mature luminal cells. Our study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in BRCA1 mutation carriers.Research.

Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

“…When these progenitors differentiated eventually, there was a basal bias. The bias in HR cKit + cells aligns conceptually with reports describing basal cancer cells of origin as luminal progenitor cells [9][10][11][12] , which were shown to be expanded in BRCA1 mut carriers 9 . Single-cell RNA-sequencing (RNA-seq) also revealed the expansion of cKit luminal progenitors with acquired basal properties in the tumors and adjacent tissue of BRCA1 mut carriers 12 .…”

“…The bias in HR cKit + cells aligns conceptually with reports describing basal cancer cells of origin as luminal progenitor cells [9][10][11][12] , which were shown to be expanded in BRCA1 mut carriers 9 . Single-cell RNA-sequencing (RNA-seq) also revealed the expansion of cKit luminal progenitors with acquired basal properties in the tumors and adjacent tissue of BRCA1 mut carriers 12 . The differentiation defect we observed in HR cKit + cells also aligns with the aberrant phenotype reported in luminal progenitors carrying a BRCA1 mut described previously 9 .…”

“…Differentiation defects in cKit + progenitors seem to be a common property of epithelia from women who are susceptible to cancer initiation, from either aging or underlying genetic risk. Luminal cancers are thought to arise from mature luminal cells and triple-negative breast cancers (TNBCs) are thought to arise from cKit + progenitors [9][10][11][12] . We speculate that the differentiation defect observed in HR and AR older progenitors is a common point of convergence on the path of cancer susceptibility and initiation, and that they later diverge to produce the different subtypes of cancer (for example, TNBCs in BRCA1 mut37 , and luminal B in BRCA2 mut and PALB2 mut37,38 ).…”

“…We defined this agedependent state as loss of lineage fidelity, in which luminal epithelia gain some characteristics of the myoepithelia while still retaining hallmark characteristics of luminal epithelial cells 8 . The phenotypic changes that occur in the luminal epithelia merit careful attention because cKit progenitors and more mature luminal cells are the putative breast cancer cells of origin 6,[9][10][11][12] . Whether loss of fidelity is explicitly related to aging or more broadly related to cancer susceptibility is not known.…”

Pre-neoplastic stromal cells drive BRCA1-mediated breast tumorigenesis

“…Many other studies have characterized BRCA1 +/mut pre-neoplastic tissues including using scRNAseq 3,4,33,36,41,42 . While these studies primarily focused on epithelial cells, our current work revealed the distinct pre-neoplastic changes within various stromal cell populations such as preCAFs.…”