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A common human PCSK9 germline variant drives breast cancer metastasis via the LRP1 receptor

ABSTRACT: Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 (rs562556) that associates with reduced breast cancer survival outcomes in multiple cohorts. Genetic modeling of this gain-of-function single nucleotide variant in mice revealed that it causally promoted breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and increased proliferative competence by targeting tumoral LRP1 receptors which repress metastasis-promoting genes. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. rs562556 stratified women in a large Swedish early-stage breast cancer cohort into those with 98% versus 78% distant-metastasis-free interval at 15 years after diagnosis. Our findings reveal that a commonly inherited genetic alteration predicts breast cancer survival and governs breast cancer metastasis—uncovering a hereditary basis underlying a prevalent cause of mortality.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Soren Heissel

LAB HEAD: Sohail F Tavazoie

PROVIDER: PXD049279 | Pride | 2024-12-05

REPOSITORIES: Pride

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			Action	DRS
	MS238145QEHF_Wenbin_Tavazoie_PM_BSA_01_b.raw	Raw
	MS238145QEHF_Wenbin_Tavazoie_PM_BSA_02_b.raw	Raw
	MS238145QEHF_Wenbin_Tavazoie_PM_BSA_03_b.raw	Raw
	MS238145QEHF_Wenbin_Tavazoie_PM_BSA_04_b.raw	Raw
	MS238145QEHF_Wenbin_Tavazoie_PM_PCSK9_01_b.raw	Raw

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