Modification of BRCA1-associated breast cancer risk by HMMR overexpression

Francesca Mateo, Zhengcheng He, Lin Mei, Gorka Ruiz de Garibay, Carmen Herranz, Nadia García, Amanda Lorentzian, Alexandra Baiges, Eline Blommaert, Antonio Gómez, Oriol Mirallas, Anna Garrido-Utrilla, Luis Palomero, Roderic Espín, Ana I. Extremera, M. Teresa Soler-Monsó, Anna Petit, Rong Li, Joan Brunet, Ke Chen, Susanna Tan, Connie J. Eaves, Curtis McCloskey, Razq Hakem, Rama Khokha, Philipp F. Lange, Conxi Lázaro, Christopher A. Maxwell () and Miquel Angel Pujana ()
Additional contact information
Francesca Mateo: L’Hospitalet del Llobregat
Zhengcheng He: University of British Columbia
Lin Mei: University of British Columbia
Gorka Ruiz de Garibay: L’Hospitalet del Llobregat
Carmen Herranz: L’Hospitalet del Llobregat
Nadia García: L’Hospitalet del Llobregat
Amanda Lorentzian: University of British Columbia
Alexandra Baiges: L’Hospitalet del Llobregat
Eline Blommaert: L’Hospitalet del Llobregat
Antonio Gómez: University of Vic – Central University of Catalonia (UVic-UCC), Vic
Oriol Mirallas: L’Hospitalet del Llobregat
Anna Garrido-Utrilla: L’Hospitalet del Llobregat
Luis Palomero: L’Hospitalet del Llobregat
Roderic Espín: L’Hospitalet del Llobregat
Ana I. Extremera: L’Hospitalet del Llobregat
M. Teresa Soler-Monsó: University Hospital of Bellvitge, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Anna Petit: University Hospital of Bellvitge, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Rong Li: The George Washington University
Joan Brunet: Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI)
Ke Chen: University of British Columbia
Susanna Tan: British Columbia Cancer Agency
Connie J. Eaves: British Columbia Cancer Agency
Curtis McCloskey: University Health Network
Razq Hakem: University Health Network
Rama Khokha: University Health Network
Philipp F. Lange: University of British Columbia
Conxi Lázaro: Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat
Christopher A. Maxwell: University of British Columbia
Miquel Angel Pujana: L’Hospitalet del Llobregat

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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-κB 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.

Date: 2022
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DOI: 10.1038/s41467-022-29335-z

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