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.
|Number of pages
|Published - 2021
Bibliographical noteFunding 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.
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- Mammary tumor
- Single cell RNA-seq
- Tumor heterogeneity
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Pharmacology, Toxicology and Pharmaceutics (miscellaneous)