Modification of BRCA1-associated breast cancer risk by HMMR overexpression

Francesca Mateo, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Zhengcheng He, Department of Pediatrics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada.
Lin Mei, Department of Pediatrics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada.
Gorka Ruiz de Garibay, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Carmen Herranz, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Nadia García, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Amanda Lorentzian, Department of Pediatrics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada.
Alexandra Baiges, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Eline Blommaert, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Antonio Gómez, Department of Biosciences, Faculty of Sciences and Technology (FCT), University of Vic - Central University of Catalonia (UVic-UCC), Vic, 08500, Barcelona, Catalonia, Spain.
Oriol Mirallas, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Anna Garrido-Utrilla, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Luis Palomero, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Roderic Espín, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Ana I. Extremera, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
M Teresa Soler-Monsó, Department of Pathology, University Hospital of Bellvitge, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Anna Petit, Department of Pathology, University Hospital of Bellvitge, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Rong Li, Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20037, USA.
Joan Brunet, Hereditary Cancer Program, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), 17190, Girona, Catalonia, Spain.
Ke Chen, Department of Pediatrics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada.
Susanna Tan, Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
Connie J. Eaves, Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
Curtis McCloskey, Princess Margaret Cancer Research Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
Razq Hakem, Princess Margaret Cancer Research Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
Rama Khokha, Princess Margaret Cancer Research Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
Philipp F. Lange, Department of Pathology, University of British Columbia, Vancouver, BC, V6T 1Z7, Canada.
Conxi Lázaro, Hereditary Cancer Program, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain.
Christopher A. Maxwell, Department of Pediatrics, University of British Columbia, Vancouver, BC, V6H 0B3, Canada. cmaxwell@bcchr.ubc.ca.
Miquel Angel Pujana, ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain. mapujana@iconcologia.net.

Document Type

Journal Article

Publication Date

4-7-2022

Journal

Nature communications

Volume

13

Issue

1

DOI

10.1038/s41467-022-29335-z

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.

Department

Biochemistry and Molecular Medicine

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