A single‐cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast

To examine global changes in breast heterogeneity across different states, we determined the single‐cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1 +/– tissue, the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the...

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Vydáno v:	The EMBO journal Ročník 40; číslo 11; s. e107333 - n/a
Hlavní autoři:	Pal, Bhupinder, Chen, Yunshun, Vaillant, François, Capaldo, Bianca D, Joyce, Rachel, Song, Xiaoyu, Bryant, Vanessa L, Penington, Jocelyn S, Di Stefano, Leon, Tubau Ribera, Nina, Wilcox, Stephen, Mann, Gregory B, Papenfuss, Anthony T, Lindeman, Geoffrey J, Smyth, Gordon K, Visvader, Jane E
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.06.2021 Springer Nature B.V John Wiley and Sons Inc
Témata:	BRCA1 carriers BRCA1 protein Breast cancer Breast Neoplasms - classification Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Carcinogenesis - genetics Carcinogenesis - metabolism Carcinogenesis - pathology CD8 antigen CD8-Positive T-Lymphocytes - metabolism Clonal selection Copy number Cycles EMBO03 EMBO19 EMBO22 ErbB-2 protein Estrogen receptors Estrogens Female Fibroblasts Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Genetic Heterogeneity Heterogeneity Humans Immunoregulation Immunotherapy Leukocyte migration LN metastasis Lymph nodes Lymphatic system Lymphocytes Lymphocytes T Macrophages Mammary gland Mammary glands Mammary Glands, Human - cytology Mammary Glands, Human - metabolism Mammary Glands, Human - pathology Menopause Metastases microenvironment Microenvironments Mutation Preneoplasia Receptors Resource RNA-Seq Single-Cell Analysis single‐cell RNA‐seq Stroma Transcriptomes Tumor cells Tumor Microenvironment Tumors microenvironment single‐cell RNA‐seq breast cancer carriers LN metastasis single-cell RNA-seq BRCA1 carriers
ISSN:	0261-4189, 1460-2075, 1460-2075
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Shrnutí:	To examine global changes in breast heterogeneity across different states, we determined the single‐cell transcriptomes of > 340,000 cells encompassing normal breast, preneoplastic BRCA1 +/– tissue, the major breast cancer subtypes, and pairs of tumors and involved lymph nodes. Elucidation of the normal breast microenvironment revealed striking changes in the stroma of post‐menopausal women. Single‐cell profiling of 34 treatment‐naive primary tumors, including estrogen receptor (ER) + , HER2 + , and triple‐negative breast cancers, revealed comparable diversity among cancer cells and a discrete subset of cycling cells. The transcriptomes of preneoplastic BRCA1 +/– tissue versus tumors highlighted global changes in the immune microenvironment. Within the tumor immune landscape, proliferative CD8 + T cells characterized triple‐negative and HER2 + cancers but not ER + tumors, while all subtypes comprised cycling tumor‐associated macrophages, thus invoking potentially different immunotherapy targets. Copy number analysis of paired ER + tumors and lymph nodes indicated seeding by genetically distinct clones or mass migration of primary tumor cells into axillary lymph nodes. This large‐scale integration of patient samples provides a high‐resolution map of cell diversity in normal and cancerous human breast. Synopsis To examine global changes in breast heterogeneity across different states, this gene expression resource integrates large‐scale patient samples from diverse tissue states and breast cancer subtypes, offering a refined high‐resolution map of cell diversity in the normal and cancerous human mammary gland. Single‐cell transcriptome analyses profile > 340,000 cells encompassing normal breast, preneoplastic BRCA1 +/– tissue, the major breast cancer subtypes, and metastatic lymph nodes. Pre‐ to post‐menopause transition is associated with marked stromal changes, with decreased PDGFRb and matrix‐associated genes in fibroblasts. Progression from preneoplasia to tumors correlates with increased immune infiltration in BRCA1 mutation carriers. Tumor epithelial compartments show comparable diversity in different breast cancer subtypes. Cycling CD8 + T‐cells are reduced in estrogen receptor (ER) + tumors, suggesting different immunoregulatory patterns. Both clonal selection and mass migration contribute to lymph node metastases in patients with ER + cancer. Graphical Abstract A large‐scale gene expression resource integrates diverse tissue samples and reveals unexpected heterogeneity of breast cancer subtypes.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work These authors jointly supervised this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.2020107333