Single-cell RNA sequencing reveals the cellular origin and evolution of breast cancer

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. Researchers from Peking University Cancer Hospital 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 BRCA1 mutation carriers and three noncarriers. Whole-exome sequencing was performed on breast tumors from the four BRCA1 mutation carriers; for validation, bulk RNA-seq was performed on adjacent normal breast tissues from eight additional BRCA1 mutation carriers and 14 noncarriers. 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 noncarriers. These observations were further validated by the bulk RNA-seq 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. This study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in BRCA1 mutation carriers.

Overview of the study design

ANM, adjacent normal mammary tissue; BC, breast cancer tissue; CNM, contralateral normal mammary tissue; NC, normal breast tissues from noncarriers served as normal control. The BRCA1 carriers were matched with noncarriers in age and parity status