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Related Experiment Video

Updated: Jun 5, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.

Wenbin Mei1, Schayan Faraj Tabrizi1, Christopher Godina2

  • 1Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.

Cell
|December 10, 2024
PubMed
Summary
This summary is machine-generated.

A common genetic variant in PCSK9 (proprotein convertase subtilisin/kexin type 9) significantly increases breast cancer metastasis risk and predicts poor survival. Inhibiting PCSK9 may offer a therapeutic strategy against cancer spread.

Keywords:
LRP1PCSK9USP18XAF1breast cancergeneticknockinmetastasisprognostictherapy

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Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Identifying patients at risk for metastatic relapse is crucial for effective breast cancer management.
  • The role of genetic factors in breast cancer metastasis is an area of active research.

Purpose of the Study:

  • To investigate the role of a common germline variant in PCSK9 (rs562556, V474I) in breast cancer metastasis and patient survival.
  • To explore the mechanistic link between PCSK9, LRP1, and metastasis-promoting genes.

Main Methods:

  • Genetic modeling in mice to assess the causal role of the PCSK9 variant in metastasis.
  • Analysis of breast cancer patient cohorts to correlate the PCSK9 variant with survival and relapse.
  • Investigating the molecular targets of PCSK9 in metastasis, including LRP1 and downstream genes.

Main Results:

  • The PCSK9 V474I variant (rs562556) was associated with reduced survival and causally promoted breast cancer metastasis in mouse models.
  • Host PCSK9 deletion reduced metastatic colonization by targeting tumoral LRP1 receptors, repressing metastasis-promoting genes.
  • Antibody-mediated PCSK9 inhibition suppressed metastasis in preclinical models.
  • In a Swedish cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse versus 2% for non-homozygotes.

Conclusions:

  • A common inherited genetic alteration in PCSK9 governs breast cancer metastasis and predicts patient survival.
  • PCSK9 acts through LRP1 to regulate metastasis-promoting genes, representing a potential therapeutic target.
  • This study uncovers a hereditary basis for breast cancer metastasis.