Student Theses and Dissertations
Date of Award
2025
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Sohail Tavazoie
Keywords
metastasis, PCSK9, breast cancer, germline variant, LRP1, tumors
Abstract
Metastasis formation is the most critical determinant of cancer survival outcome. Identifying patients at risk for metastatic relapse facilitates clinical decision and the use of appropriate adjuvant therapy, thus having a profound impact on patient survival. A central dogma in cancer is that during tumorigenesis, cancer cells acquire somatic mutations that regulate metastatic likelihood during evolution of the primary tumor. However, despite extensive tumor sequencing efforts, such causal somatic metastasis driver mutations have not been found, limiting the discovery of biomarkers, mechanisms and drug targets of cancer metastasis. In this thesis, I report a germline genetic driver of breast cancer metastasis, suggesting that germline genetic differences between individuals underlie distinct metastatic outcomes. I identified a common missense germline variant in PCSK9 (rs562556, V474I) that associates with reduced survival in breast cancer cohorts from multiple countries. This highly prevalent variant is homozygous in ~70% of people of European ancestry. 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 LRP1 receptors, which signaled to the nucleus and repressed metastasis-promoting genes XAF1 and USP18. Mechanistically, the V474I mutation may enhance PCSK9's suppression of LRP1 by increasing its binding affinity. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in a variety of murine, human, transplantable, and genetically initiated models. These findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival—uncovering a hereditary basis underlying breast cancer metastasis. My work also highlighted the therapeutic potential of PCSK9-inhibitory therapy, which has been approved by more than 75 countries, for the prevention and treatment of metastatic breast cancer.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Mei, Wenbin, "Germline Genetic Modulator of Cancer Metastasis" (2025). Student Theses and Dissertations. 816.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/816
Comments
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy