Single-Cell RNA Sequencing Reveals the Cellular Origin and Evolution of Breast Cancer in <i>BRCA1</i> Mutation Carriers.

Abstract

The cell of origin and the development of breast cancer are not fully elucidated in <i>BRCA1</i> mutation carriers, especially for estrogen receptor (ER)-positive breast cancers. Here, we performed single-cell RNA sequencing (RNA-seq) on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four <i>BRCA1</i> mutation carriers and three noncarriers. Whole-exome sequencing was performed on breast tumors from the four <i>BRCA1</i> mutation carriers; for validation, bulk RNA-seq was performed on adjacent normal breast tissues from eight additional <i>BRCA1</i> mutation carriers and 14 noncarriers. Correlation analyses suggested that breast cancers in <i>BRCA1</i> mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in <i>BRCA1</i> mutation carriers compared with noncarriers. These observations were further validated by the bulk RNA-seq data from additional <i>BRCA1</i> mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ER^neg) in <i>BRCA1</i> mutation carriers might be luminal progenitor cells. The expression of <i>TP53</i> and <i>BRCA1</i> was decreased in luminal progenitor cells from normal breast tissue in <i>BRCA1</i> 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 <i>BRCA1</i> mutation carriers. SIGNIFICANCE: Single-cell RNA-seq data indicate that basal-like breast cancer (ER^neg) might originate from luminal progenitors, and ER^high luminal breast cancer might originate from mature luminal cells in <i>BRCA1</i> mutation carriers.