Genetic associations of plasma proteins and breast cancer identify potential therapeutic drug candidates

Abstract

To address the pressing need to improve breast cancer outcomes, we identify 9 plasma proteins with significant associations to breast cancer, namely ULK3, CSK, ASIP, TLR1 in breast cancer, ADH5, SARS2, ULK3, UBE2N in Luminal A subtype, PEX14 in Luminal B subtype. Tumor immune cell infiltration analysis and mutation phenotypes in mice further demonstrate a complex pattern of interaction between these genes and immune responses. Compared to normal tissues, tumor tissues exhibit reduced expression of ULK3 and CSK. Notably, elevated ULK3 expression in both breast cancer and the Luminal A subtype is significantly associated with prolonged recurrence-free survival. Overexpression of CSK and ULK3 is confirmed to significantly inhibit the proliferation and migratory ability of MCF-7 cells. Additionally, three drug candidates-TG100801, Hydrochlorothiazide, and Imatinib-show promise in targeting these proteins, contributing valuable insights for prioritizing drug development in realm of breast cancer.

Fig. 1. The mendelian analysis and colocalization analysis results between plasma proteins and breast cancer.

a The identified gene proteins after colocalization analysis and mendelian analysis. * & # stand different probes in the Decode database: *13094_75 #8427_118 PH4 posterior probability of H4. The diagram depicts concentric circles, with each circle’s distinct coloration corresponding to specific groups. The innermost circle denotes different groups, while the middle circle signifies the colocalization result, and the outermost circle represents the TSMR result. Color gradients, ranging from red to blue, symbolize β values spanning from −0.05 to 0.5. In this gradient, red signifies protective factors, whereas blue indicates risk factors. b Manhattan plots for identified 62 circulating proteins in mendelian analysis stage. Results are plotted by gene start position. Each point signifies an individual association test between a gene and breast cancer, arranged by genomic position on the x-axis and association strength on the y-axis, represented as the −log10(P) of a z-score test.

Fig. 2. Pathway analysis of identified proteins associated with breast cancer.

a KEGG pathway enrichment analysis of identified proteins associated with breast cancer. b DO disease categorization analysis of identified proteins associated with breast cancer. c GO biological process analysis of identified proteins associated with breast cancer. BP biological processes, CC cellular components, MF molecular functions.

Fig. 3

Overall and recurrence free survival analysis of identified plasma proteins with high support in breast cancer.

Fig. 4

Overall and recurrence free survival analysis of identified plasma proteins with high support in Luminal breast cancer.

Fig. 5

Discovered drug targeting identified plasma proteins with robust support in breast cancer.

Fig. 6. Immunohistochemical analysis of CSK, ULK3, and ADH5 expression in Luminal A breast cancer tissues.

a Representative images showing CSK, ULK3, and ADH5 expression in Luminal A breast cancer tissues and adjacent normal tissues. Positive staining is indicated by brown coloration. b Quantitative analysis of protein expression in tumor and adjacent tissues in Luminal A breast cancer. Quantification of CSK, ULK3, and ADH5 expression levels in cancer tissues compared to normal tissues. AOD average optical density, T tumor, N normal. *P < 0.05, **P < 0.01, ***P < 0.001. Data are presented as mean ± standard deviation. (N = 25 biologically independent samples).

Fig. 7. Effects of CSK and ULK3 overexpression on the proliferation and migration of MCF-7 cells.

a, b CSK and ULK3 were significantly overexpressed in MCF-7 cells 24 hours after lentiviral transfection. c Cell proliferation was assessed using the CCK-8 assay at 24, 48, 72, and 96 hours in MCF-7 cells overexpressing CSK and ULK3b (N = 5 per group). d–g Cell migration was evaluated using a wound healing assay in MCF-7 cells overexpressing CSK and ULK3 at 24 hours. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 8. Schematic diagram of this study.

GWAS genome-wide association study, pQTL protein quantitative trait loci, cis-pQTL cis-acting protein quantitative trait loci, MHC major histocompatibility complex, LD linkage disequilibrium, MR Mendelian randomization, SMR summary-data-based MR test, HEIDI heterogeneity in dependent instrument, PH4 posterior probability of H4, GEO Gene Expression Omnibus, EGA European Genome-Phenome Archive, TCGA The Cancer Genome Atlas, Metabric Molecular Taxonomy of Breast Cancer International Consortium. (Created in BioRender. quan, l. (2025) https://BioRender.com/ cdz72yh).