4.7 Article

In vivo genome-editing screen identifies tumor suppressor genes that cooperate with Trp53 loss during mammary tumorigenesis

期刊

MOLECULAR ONCOLOGY
卷 16, 期 5, 页码 1119-1131

出版社

WILEY
DOI: 10.1002/1878-0261.13179

关键词

axin1; breast cancer; CRISPR; Cas9; intraductal; mammary organoids; Prkar1a; Trp53

类别

资金

  1. Australian National Health and Medical Research Council (NHMRC) [1113133, 1054618, 1143105]
  2. Cancer Council Victoria Venture Grant
  3. NHMRC IRIISS
  4. Victorian State Government through VCA
  5. Australian Cancer Research Foundation
  6. Breast Cancer Research Foundation
  7. VCA ECRF [19011]
  8. NHMRC Investigator Grants/Fellowships [1116937, 1156095, 1176199, 1058892, 1078730, 1175960, 1037230, 1102742]
  9. National Health and Medical Research Council of Australia [1116937, 1156095, 1175960, 1102742, 1078730, 1058892] Funding Source: NHMRC

向作者/读者索取更多资源

Breast cancer is a heterogeneous disease with multiple histological and molecular subtypes. This study describes a pipeline for identifying and validating tumor suppressor genes in breast cancer. Through in vivo and ex vivo experiments, several tumor suppressor genes were identified. The mutations in these genes were shown to accelerate tumor development in breast cancer.
Breast cancer is a heterogeneous disease that comprises multiple histological and molecular subtypes. To gain insight into mutations that drive breast tumorigenesis, we describe a pipeline for the identification and validation of tumor suppressor genes. Based on an in vivo genome-wide CRISPR/Cas9 screen in Trp53(+/-) heterozygous mice, we identified tumor suppressor genes that included the scaffold protein Axin1, the protein kinase A regulatory subunit gene Prkar1a, as well as the proof-of-concept genes Pten, Nf1, and Trp53 itself. Ex vivo editing of primary mammary epithelial organoids was performed to further interrogate the roles of Axin1 and Prkar1a. Increased proliferation and profound changes in mammary organoid morphology were observed for Axin1/Trp53 and Prkar1a/Trp53 double mutants compared to Pten/Trp53 double mutants. Furthermore, direct in vivo genome editing via intraductal injection of lentiviruses engineered to express dual short-guide RNAs revealed that mutagenesis of Trp53 and either Prkar1a, Axin1, or Pten markedly accelerated tumor development compared to Trp53-only mutants. This proof-of-principle study highlights the application of in vivo CRISPR/Cas9 editing for uncovering cooperativity between defects in tumor suppressor genes that elicit mammary tumorigenesis.

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