Ductal keratin 15+ luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature

Normal breast luminal epithelial progenitors have been implicated as cell of origin in basal-like breast cancer, but their anatomical localization remains understudied. Here, we combine micro-collection of uncultured organoids and single cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal ductal lobular units (TDLUs) and compare them with breast cancer subtypes. Unsupervised clustering reveals eleven distinct clusters and a differentiation trajectory starting with keratin 15+ (K15+) progenitors enriched in ducts. Spatial mapping of luminal progenitors is confirmed at the protein level by staining with critical duct markers. Comparison of the gene expression profiles of normal luminal cells with those of breast cancer subtypes reveals a strong correlation between normal breast K15+ ductal progenitors and basal-like breast cancer. We propose that K15+ basal-like breast cancers originate in ductal progenitors, which emphasizes the importance of not only lineages but also cellular position within the ductal-lobular tree.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 2 Publications

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Dataset ID	Description	Technology	Samples
EGAD00001008499	The dataset includes 12 paired FASTQ files (6 samples) with single cell transcriptome sequencing data of normal breast luminal cells from ducts and TDLUs derived from reduction mammoplasties from three patients. Chromium Single Cell 3’ Reagent Kit v2 or v3 (10x Genomics) were used for processing of cells, whereafter sequencing was performed using the Illumina® NextSeq500/550 High Output Kit v2. Cell Ranger was used for generating FASTQ files and files from different lanes were concatenated prior to uploading the data to EGA. "R1" files include the feature barcodes and UMIs, while "R2" files include the reads.	NextSeq 550	6

Publications	Citations
Ductal keratin 15<sup>+</sup> luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature. Kohler KT, Goldhammer N, Demharter S, Pfisterer U, Khodosevich K, Rønnov-Jessen L, Petersen OW, Villadsen R, Kim J. NPJ Breast Cancer 8: 2022 81	7
Oncogene activated human breast luminal progenitors contribute basally located myoepithelial cells. Kohler KT, Kim J, Villadsen R, Rønnov-Jessen L, Petersen OW. Breast Cancer Res 26: 2024 183	0