Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal pro...

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Published in:	Cell reports (Cambridge) Vol. 35; no. 2; p. 108945
Main Authors:	Valdés-Mora, Fátima, Salomon, Robert, Gloss, Brian Stewart, Law, Andrew Man Kit, Venhuizen, Jeron, Castillo, Lesley, Murphy, Kendelle Joan, Magenau, Astrid, Papanicolaou, Michael, Rodriguez de la Fuente, Laura, Roden, Daniel Lee, Colino-Sanguino, Yolanda, Kikhtyak, Zoya, Farbehi, Nona, Conway, James Ronald William, Sikta, Neblina, Oakes, Samantha Richelle, Cox, Thomas Robert, O’Donoghue, Seán Ignatius, Timpson, Paul, Ormandy, Christopher John, Gallego-Ortega, David
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 13-04-2021 Elsevier
Subjects:	alveolar lineage Animals basal breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology cancer-associated fibroblast Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Carcinoma, Basal Cell - genetics Carcinoma, Basal Cell - metabolism Carcinoma, Basal Cell - pathology Cell Lineage - genetics Chemokine CXCL12 - genetics Chemokine CXCL12 - metabolism Collagen Type I, alpha 1 Chain - genetics Collagen Type I, alpha 1 Chain - metabolism Elf5 Extracellular Matrix - metabolism Extracellular Matrix - pathology Female Gene Expression Regulation, Neoplastic High-Throughput Nucleotide Sequencing Humans involution mammary gland epithelial hierarchy Mammary Glands, Animal - metabolism Mammary Glands, Animal - pathology Mammary Glands, Animal - virology Mammary Neoplasms, Animal - genetics Mammary Neoplasms, Animal - metabolism Mammary Neoplasms, Animal - pathology Mammary Tumor Virus, Mouse - growth & development Mammary Tumor Virus, Mouse - pathogenicity Matrix Metalloproteinase 3 - genetics Matrix Metalloproteinase 3 - metabolism Mice Neoplasm Metastasis Pregnancy pregnancy-associated breast cancer scRNA-seq Single-Cell Analysis Transcriptome Tumor Microenvironment - genetics cancer-associated fibroblast alveolar lineage scRNA-seq Elf5 basal breast cancer mammary gland epithelial hierarchy pregnancy-associated breast cancer involution
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Summary:	Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth. [Display omitted] •Drop-seq reveals a strong cancer cell heterogeneity in PyMT mammary tumors•Elf5 redefines cancer cell states toward basal-like with pro-metastatic features•PyMT/Elf5 tumors show cellular and molecular characteristics of involution mimicry•Involution CAFs in PyMT/Elf5 tumors interconnect the TME and cancer cells Using single-cell transcriptomics, Valdés-Mora et al. show that Elf5 drives alveolar lineage differentiation in PyMT tumors, resulting in cancer cell states with basal-like characteristics and a multicellular process of unresolved lactation, with concomitant acquisition of metastasis. This study may partially explain the poor prognosis of breast cancer associated with childbirth.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2021.108945