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

Faraj Tabrizi, Schayan ; Mei, Wenbin ; Godina, Christopher LU orcid ; Lovisa, Anthea F. ; Isaksson, Karolin LU ; Jernström, Helena LU and Tavazoie, Sohail F. (2024) In Cell 188(2). p.28-389
Abstract
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... (More)
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 (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Cell
volume
188
issue
2
pages
28 - 389
publisher
Cell Press
external identifiers
  • pmid:39657676
  • scopus:85215229129
ISSN
1097-4172
DOI
10.1016/j.cell.2024.11.009
language
English
LU publication?
yes
id
bcc26939-287d-4298-a80d-625f0a0646b1
date added to LUP
2024-12-15 15:07:36
date last changed
2025-04-07 11:30:19
@article{bcc26939-287d-4298-a80d-625f0a0646b1,
  abstract     = {{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}},
  author       = {{Faraj Tabrizi, Schayan and Mei, Wenbin and Godina, Christopher and Lovisa, Anthea F. and Isaksson, Karolin and Jernström, Helena and Tavazoie, Sohail F.}},
  issn         = {{1097-4172}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{28--389}},
  publisher    = {{Cell Press}},
  series       = {{Cell}},
  title        = {{A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor}},
  url          = {{http://dx.doi.org/10.1016/j.cell.2024.11.009}},
  doi          = {{10.1016/j.cell.2024.11.009}},
  volume       = {{188}},
  year         = {{2024}},
}