Effect of recombinant PCSK9 treatment on the gene expression of EO771 cells
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ABSTRACT:
PROVIDER: PRJNA1075439 | ENA |
REPOSITORIES: ENA
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Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 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. This variant 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.
2024-12-09 | GSE255558 | GEO
Project description:Effect of host PCSK9 treatment on the gene expression of EO771 primary tumor
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Project description:Effect of host PCSK9 treatment on the gene expression of EO771 primary tumor [RNAseq_KI_tumor]
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Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 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. This variant 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.
2024-12-09 | GSE255560 | GEO
Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 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. This variant 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.
2024-12-09 | GSE273936 | GEO
Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 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. This variant 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.
2024-12-09 | GSE255559 | GEO
Project description:Effect of Lrp1 knockdown on the gene expression of EO771 cells
| PRJNA1075438 | ENA
Project description:Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived AQ3 from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (−38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake, whereas cells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (−89.7%; P<0.001) and had a 106% increase (P=0.0104) of LDL uptake. Pravastatin treatment significantly enhanced LDL receptor (LDLR) and PCSK9 mRNA gene expression, as well as PCSK9 secretion and LDL uptake in both control and S127R HLCs. Pravastatin treatment of multiple clones led to an average increase of LDL uptake of 2.19±0.77-fold in HLC-S127R compared to 1.38±0.49 fold in control HLCs (P<0.01), in line with the good response to statin treatment of individuals carrying the S127R mutation (mean LDL cholesterol reduction=60.4%, n=5). In conclusion, urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function.
2015-12-01 | GSE75545 | GEO
Project description:We have transfected Hep2G cells with the gain-of-function mutant D374Y-PCSK9.
2008-01-30 | E-MEXP-1235 | biostudies-arrayexpress
Project description:Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of LDL cholesterol metabolism and the target of lipid-lowering drugs. PCSK9 is mainly expressed in hepatocyte. Here, we show that PCSK9 is highly expressed in undifferentiated hiPSCs. PCSK9 inhibition in hiPSCs with the use of shRNA, CRISPR/cas9-mediated knockout or endogenous PCSK9 loss-of-function mutation R104C/V114A unveiled its new role as a potential cell cycle regulator through the NODAL signaling pathway. Indeed, PCSK9 inhibition leads to a decrease of SMAD2 phosphorylation and hiPSCs proliferation. Conversely, PCSK9 overexpression stimulates hiPSCs proliferation. PCSK9 can interfere with the NODAL pathway by regulating the expression of its endogenous inhibitor DACT2, which is involved in the TGFß-R1 lysosomal degradation. Using different PCSK9 constructs we show that PCSK9 interacts with DACT2 through its CHRD domain. Altogether these data highlight a new role of PCSK9 in cellular proliferation and development, beyond its canonical effect on lipid metabolism.
2021-08-05 | GSE181481 | GEO