A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.

Autor:	Mei W; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA., Faraj Tabrizi S; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA., Godina C; Division of Oncology, Department of Clinical Sciences in Lund, Lund University Cancer Center/Kamprad, Lund, Sweden., Lovisa AF; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA., Isaksson K; Division of Surgery, Department of Clinical Sciences in Lund, Lund University and Department of Surgery Kristianstad Hospital, Lund, Sweden., Jernström H; Division of Oncology, Department of Clinical Sciences in Lund, Lund University Cancer Center/Kamprad, Lund, Sweden., Tavazoie SF; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA. Electronic address: sohail.tavazoie@rockefeller.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Dec 09. Date of Electronic Publication: 2024 Dec 09.
DOI:	10.1016/j.cell.2024.11.009
Abstrakt:	Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis. Competing Interests: Declaration of interests S.F. Tavazoie is a cofounder, shareholder, and member of the scientific advisory board of Inspirna. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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