Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing

Heng Sun, Jianming Zeng, Zhengqiang Miao, Kuan Cheok Lei, Chen Huang, Lingling Hu, Sek Man Su, Un In Chan, Kai Miao, Xu Zhang, Aiping Zhang, Sen Guo, Si Chen, Ya Meng, Min Deng, Wenhui Hao, Haipeng Lei, Ying Lin, Zhonglin Yang, Dongjiang TangKoon Ho Wong, Xiaohua Douglas Zhang, Xiaoling Xu, Chu Xia Deng

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: BRCA1 plays critical roles in mammary gland development and mammary tumorigenesis. And loss of BRCA1 induces mammary tumors in a stochastic manner. These tumors present great heterogeneity at both intertumor and intratumor levels. Methods: To comprehensively elucidate the heterogeneity of BRCA1 deficient mammary tumors and the underlying mechanisms for tumor initiation and progression, we conducted bulk and single cell RNA sequencing (scRNA-seq) on both mammary gland cells and mammary tumor cells isolated from Brca1 knockout mice. Results: We found the BRCA1 deficient tumors could be classified into four subtypes with distinct molecular features and different sensitivities to anti-cancer drugs at the intertumor level. Whereas within the tumors, heterogeneous subgroups were classified mainly due to the different activities of cell proliferation, DNA damage response/repair and epithelial-to-mesenchymal transition (EMT). Besides, we reconstructed the BRCA1 related mammary tumorigenesis to uncover the transcriptomes alterations during this process via pseudo-temporal analysis of the scRNA-seq data. Furthermore, from candidate markers for BRCA1 mutant tumors, we discovered and validated one oncogene Mrc2, whose loss could reduce mammary tumor growth in vitro and in vivo. Conclusion: Our study provides a useful resource for better understanding of mammary tumorigenesis induced by BRCA1 deficiency.

Original languageEnglish
Pages (from-to)9967-9987
Number of pages21
JournalTheranostics
Volume11
Issue number20
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
We thank members of the Deng, Xu and Wong laboratories for helpful advice and discussion. We thank Dapeng Hao, Haitao Wang and Wei Qiao for their assistance of data analysis. We thank Yixiang Shi and Tiffany Nga Teng Iu for their assistance of scRNA-seq and dropseq. This work was supported by National Natural Science Foundation of China Grant 81602587 granted to HS, the Chair Professor Grant (CPG2019-00019-FHS and CPG2021-00021-FHS) granted to CD, Macao Science and Technology Development Fund (FDCT) grant 065/2015/A2, 0011/2019/AKP, and 0034/2019/AGJ to CD and FDCT grant 0004/2019/AFJ to XDZ, and Guangdong Science and Technology Department grant 2020A050515005 to DT.

Publisher Copyright:
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Keywords

  • Brca1/BRCA1
  • Mammary tumor
  • Mrc2
  • Single cell RNA-seq
  • Tumor heterogeneity

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Fingerprint

Dive into the research topics of 'Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing'. Together they form a unique fingerprint.

Cite this