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Title: | Modification of BRCA1-associated breast cancer risk by HMMR overexpression |
Author: | Mateo, Francesca He, Zhengcheng Mei, Lin Ruiz de Garibay, Gorka Herranz, Carmen García, Nadia Lorentzian, Amanda Baiges, Alexandra Blommaert, Eline Gómez, Antonio Mirallas, Oriol Garrido Utrilla, Anna Palomero, Luis Espín, Roderic Extremera, Ana I. Soler Monsó, M. Teresa Petit, Anna Li, Rong Brunet, Joan Chen, Ke Tan, Susanna Eaves, Connie J. Mccloskey, Curtis Hakem, Razq Khokha, Rama Lange, Philipp F. Lázaro García, Conxi Maxwell, Christopher A. Pujana, Miquel Angel |
Keywords: | Càncer de mama Genètica mèdica Malalties hereditàries Breast cancer Medical genetics Genetic diseases |
Issue Date: | 7-Apr-2022 |
Publisher: | Springer Science and Business Media LLC |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-29335-z |
It is part of: | Nature Communications, 2022, vol. 13, num. 1895 |
URI: | http://hdl.handle.net/2445/185171 |
Related resource: | https://doi.org/10.1038/s41467-022-29335-z |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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s41467-022-29335-z.pdf | 6.34 MB | Adobe PDF | View/Open |
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