Ductal keratin 15+ luminal progenitors in normal breast exhibit a basal-like breast cancer transcriptomic signature
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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 collection under the microscope of organoids from reduction mammoplasties and single-cell mRNA sequencing (scRNA-seq) of FACS-sorted luminal epithelial cells with multicolor imaging to profile ducts and terminal duct 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 suggests a strong correlation between normal breast 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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 81 |
| Tidsskrift | npj Breast Cancer |
| Vol/bind | 8 |
| Udgave nummer | 1 |
| Antal sider | 12 |
| ISSN | 2374-4677 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
We thank Tove Marianne Lund, Lena Kristensen, and Anita Sharma Friismose for excellent technical assistance. Capio CFR Hospitaler (Benedikte Thuesen and Trine Foged Henriksen) and the donors are acknowledged for providing breast biopsy material. The Core Facility for Integrated Microscopy (University of Copenhagen) is acknowledged for confocal microscope accessibility. We thank Gelo Dela Cruz and the DanStem Flow Cytometry Platform for access to FCS Express to analyze flow cytometry data. Furthermore, we thank Helen Neil and the DanStem Genomics Platform for technical expertize, support, and the use of instruments. This work was supported by Novo Nordisk Fonden (NNF17CC0027852) and Danish Research Council grant 10-092798 (to DanStem), Familien Erichsens Mindefond and Vera og Carl Johan Michaelsens Legat (to J.K.), Toyota-Fonden Denmark and Anita og Tage Therkelsens Fond (to R.V.), Dagmar Marshalls Fond (to L.R.-J.), Novo Nordisk Fonden (NNF18CC0033666 (to N.G.), the Kirsten and Freddy Johansens Fond, Agnes and Poul Friis Fond (to O.W.P.).
Funding Information:
We thank Tove Marianne Lund, Lena Kristensen, and Anita Sharma Friismose for excellent technical assistance. Capio CFR Hospitaler (Benedikte Thuesen and Trine Foged Henriksen) and the donors are acknowledged for providing breast biopsy material. The Core Facility for Integrated Microscopy (University of Copenhagen) is acknowledged for confocal microscope accessibility. We thank Gelo Dela Cruz and the DanStem Flow Cytometry Platform for access to FCS Express to analyze flow cytometry data. Furthermore, we thank Helen Neil and the DanStem Genomics Platform for technical expertize, support, and the use of instruments. This work was supported by Novo Nordisk Fonden (NNF17CC0027852) and Danish Research Council grant 10-092798 (to DanStem), Familien Erichsens Mindefond and Vera og Carl Johan Michaelsens Legat (to J.K.), Toyota-Fonden Denmark and Anita og Tage Therkelsens Fond (to R.V.), Dagmar Marshalls Fond (to L.R.-J.), Novo Nordisk Fonden (NNF18CC0033666 (to N.G.), the Kirsten and Freddy Johansens Fond, Agnes and Poul Friis Fond (to O.W.P.).
Publisher Copyright:
© 2022, The Author(s).
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