A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast
journal contributionposted on 13.07.2021, 04:21 authored by Bhupinder PalBhupinder Pal, Y Chen, F Vaillant, BD Capaldo, R Joyce, X Song, VL Bryant, JS Penington, L Di Stefano, N Tubau Ribera, S Wilcox, GB Mann, AT Papenfuss, GJ Lindeman, GK Smyth, JE Visvader
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.
We are grateful to S Nutt, D Gray, and L Whitehead for discussions, H.K. Liu and E Surgenor for expert assistance, the Imaging and FACS facilities at WEHI, Leanne Taylor and colleagues from the Royal Melbourne Hospital Tissue Bank and the Victorian Cancer Biobank, Heather Thorne and all contributors to the Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer (kConFab). This work was supported by the National Breast Cancer Foundation (NBCF, IIRS-20-022), Australian National Health and Medical Research Council (NHMRC) grants (#1054618, 1100807, 1113133, 1153049); NHMRC IRIISS; the Victorian State Government Operational Infrastructure Support; the Australian Cancer Research Foundation and the Ian Potter Foundation. G.J.L., G.K.S. and J.E.V. were supported by NHMRC Fellowships (G.J.L. #1078730 and 1175960; G.K.S. #1058892; J.E.V. #1037230 and 1102742).
Article NumberARTN e107333
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Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyCell BiologyBRCA1 carriersbreast cancerLN metastasismicroenvironmentsingle‐cell RNA‐seqDNA-SEQUENCING REVEALSCANCERTUMORHETEROGENEITYMODELMECHANISMSLANDSCAPERESPONSESDISEASEGENESkConFabsingle-cell RNA-seqDevelopmental Biology