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.

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<p>Table S1. Detailed information on the BRCA1 germline mutation and clinicopathological characteristics of seven patients; Table S2. Cell numbers detected by single cell RNA-seq; Table S3. List of cell type specific marker genes identified at a single cell resolution; Table S4. EMT signature gene set; Table S5. Clinicopathologic information of 8 additional BRCA1 mutation carriers and 14 non-carriers for bulk RNA-seq; Table S6. Clinico-pathologic information of the breast cancers from BRCA1/2 germline mutation carriers from The Cancer Genome Atlas (TCGA) database included in this study for comparisons; Table S7. Clinicopathologic information of 7 BRCA1 mutation carriers and 10 non-carriers whose samples for immunohistochemistry staining.</p>

<p>Table S9. Oncogenic mutations detected in the breast tumor tissues from four BRCA1 mutation carriers.</p>