4.8 Article

Modification of BRCA1-associated breast cancer risk by HMMR overexpression

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29335-z

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资金

  1. University of Barcelona-Bellvitge Animal Facility
  2. patient foundation in Catalonia (DACMA)
  3. patient foundation in Catalonia (GINKGO)
  4. patient foundation in Catalonia (Viladecans Contra el Cancer)
  5. patient foundation in Catalonia (Toca-te-les)
  6. Instituto de Salud Carlos III [PI16/00563, PI18/01029, PI19/00553, PI21/01306]
  7. CIBERONC - (European Regional Development Fund. ERDF, a way to build Europe)
  8. CIBERES - (uropean Regional Development Fund. ERDF, a way to build Europe)
  9. Generalitat de Catalunya [SGR 2017-449, 2017-1282]
  10. Generalitat de Catalunya (PERIS PFI-Salut) [SLT017-20-000076]
  11. Generalitat de Catalunya (Suport) [SLT017/20/000072]
  12. Generalitat de Catalunya (MedPerCan)
  13. Generalitat de Catalunya (URDCat)
  14. La Marato de TV3 2019 [240]
  15. CERCA Program
  16. Canadian Institutes of Health Research [169111]
  17. Canadian Cancer Society [BC-RG-16]
  18. Michael Cuccione Foundation for Childhood Cancer Research
  19. BC Children's Hospital Research Institute
  20. Murray Family
  21. University of British Columbia 4-year fellowship program
  22. National Institute of Health [R01CA220578]

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Breast cancer risk for carriers of BRCA1 pathological variants is influenced by genetic factors, with HMMR being a potential contributor. Overexpression of HMMR has been found to increase the risk of Brca1-mutant breast cancer by modulating the cancer cell phenotype and tumor microenvironment. This study provides insight into the biological basis of increased risk for BRCA1-associated breast cancer.
Breast cancer risk for carriers of BRCA1 pathological variants is modified by genetic factors. Genetic variation in HMMR may contribute to this effect. However, the impact of risk modifiers on cancer biology remains undetermined and the biological basis of increased risk is poorly understood. Here, we depict an interplay of molecular, cellular, and tissue microenvironment alterations that increase BRCA1-associated breast cancer risk. Analysis of genome-wide association results suggests that diverse biological processes, including links to BRCA1-HMMR profiles, influence risk. HMMR overexpression in mouse mammary epithelium increases Brca1-mutant tumorigenesis by modulating the cancer cell phenotype and tumor microenvironment. Elevated HMMR activates AURKA and reduces ARPC2 localization in the mitotic cell cortex, which is correlated with micronucleation and activation of cGAS-STING and non-canonical NF-kappa B signaling. The initial tumorigenic events are genomic instability, epithelial-to-mesenchymal transition, and tissue infiltration of tumor-associated macrophages. The findings reveal a biological foundation for increased risk of BRCA1-associated breast cancer. The effect of hyaluronan-mediated motility receptor (HMMR) expression in BRCA1-associated breast cancer risk remains unknown. Here, HMMR overexpression induces the activation of cGAS-STING and non-canonical NF-kappa B signalling, instigating an immune permissive environment for breast cancer development.

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