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Accession PRJCA009018
Title Single-cell profiling of female breast fibroadenoma reveals unique epithelial cell compositions and therapeutic targets
Relevance Medical
Data types Transcriptome or Gene expression
Single cell sequencing
Organisms Homo sapiens
Description Fibroadenomas (FAs) are the most common breast tumors in women with an increased long-term risk of developing breast carcinoma. Surgical excision is the most effective therapy; however, it incurs undesirable scarring, extensive ductal damage and even local recurrence after surgery. No pharmacological agents are currently approved for FA intervention owing to its unclear mechanisms and a shortage of reproducible human models. Here, using single-cell RNA sequencing of approximately 28,000 human cells from FAs and normal breast tissues, we demonstrate the unique cellular composition and epithelial structural changes manifesting as an increase in inner mature luminal cells of the mammary gland coupled with a significant decrease in outer basal cells, which leads to loss of the normal bicell layer in FAs. Interestingly, epithelial cells exhibit hormone-responsive functional signatures and synchronous activation of estrogen-sensitive (ESR1, TFF1, TFF3) and hormone-resistant mechanisms (ERBB2, BCL2 and CCND1 pathways), which may explain why the therapeutic efficacy of the estrogen receptor modulator tamoxifen has not been ideal in clinical trials. We developed the first human expandable FA organoid system and found that most organoids were resistant to tamoxifen. Individualized combinations of tamoxifen with CCND1, BCL2 or ERBB2 inhibitors can significantly suppress the viability of tamoxifenresistant organoids. Additionally, hormone-resistant pathways (ERBB2, BCL2 and CCND1) are positively associated with the local recurrence of FAs after resection. Our study presents a comprehensive overview of human fibroadenoma at single-cell resolution that outlines the structural and functional differences between FA and normal breast epithelium and, in particular, provides a novel therapeutic strategy for breast FAs.
Sample scope Multiisolate
Release date 2023-05-16
Publication
PubMed ID Article title Journal name DOI Year
37328469 Single cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets Nature Communications 10.1038/s41467-023-39059-3 2023
Grants
Agency program Grant ID Grant title
National Natural Science Foundation of China (NSFC) 81972598
National Natural Science Foundation of China (NSFC) 32100725
Health Commission of Zhejiang Province WKJ-ZJ-1803
Natural Science Foundation of Zhejiang Province LQ20H160064
Natural Science Foundation of Zhejiang Province LGF20H160026
Fundamental Research Funds for the Central Universities 2020FZZX003-02-12
Fundamental Research Funds for the Central Universities 2021FZ203-02-08
Submitter Jian Huang (drhuangjian@zju.edu.cn)
Organization The Second Affiliated Hospital, Zhejiang University School of Medicine
Submission date 2022-04-07

Project Data

Resource name Description
BioSample (21)  show -