期刊
THERANOSTICS
卷 11, 期 20, 页码 9967-9987出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.63995
关键词
Brca1/BRCA1; single cell RNA-seq; tumor heterogeneity; mammary tumor; Mrc2
资金
- National Natural Science Foundation of China [81602587]
- Chair Professor Grant [CPG2019-00019-FHS, CPG2021-00021-FHS]
- Macao Science and Technology Development Fund (FDCT) [065/2015/A2, 0011/2019/AKP, 0034/2019/AGJ]
- FDCT [0004/2019/AFJ]
- Guangdong Science and Technology Department [2020A050515005]
The study identified four subtypes of BRCA1 deficient mammary tumors with distinct molecular features and different sensitivities to anti-cancer drugs at the intertumor level, as well as heterogeneous subgroups within the tumors mainly based on different activities of cell proliferation, DNA damage response/repair and epithelial-to-mesenchymal transition (EMT). Furthermore, through pseudo-temporal analysis of scRNA-seq data, the study reconstructed the transcriptome alterations during BRCA1 related mammary tumorigenesis and discovered an oncogene Mrc2 that could reduce mammary tumor growth in vitro and in vivo.
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.
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