GRB2 promotes malignant behaviors of breast cancer by modulating the global expression and alternative splicing profiles in SK-BR-3 cells through binding mRNA [RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE276962 | GEO | 2025/05/07
REPOSITORIES: GEO
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Project description:The flexible protein GRB2 interacts with HER1~4 on the cell surface and regulates the angiogenesis, differentiation, and proliferation of tumor cells. It is an essential component of the intricate signaling cascade of tyrosine kinase receptors. Meanwhile, GRB2 is an RBP that plays an important role in post-transcriptional regulation in eukaryotes, which affects every stage of mRNA synthesis, modification, splicing, stabilization. Research on breast cancer is limited, but one study found a connection between GRB2 and HER2-positive breast cancer, highlighting the potential of GRB2 as a novel biomarker that stimulates tumor growth. In this research endeavor, we will investigate the impact of GRB2's regulatory mechanism on metastasis in HER2-positive breast cancer.
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Project description:Dual inhibitors of HER2 and EGFR, such as lapatinib, have shown significant efficacy for the therapy of HER2-positive breast cancer. Previous experiments showed that in cell cultures, the efficacy of lapatinib was significantly reduced by exposure to human serum and human epidermal growth factor (EGF). At the proteomic and transcriptomic levels, we examined the changes in the HER2-positive breast cancer cell line SK-BR-3 profiles upon treatment with lapatinib, either alone or in combination with human serum or EGF. Proteomic profiling revealed 350 differentially expressed proteins (DEPs) in response to lapatinib treatment at concentrations that induced cell growth arrest. Addition of human serum or EGF in combination with lapatinib prevented cell growth inhibition, and this combination treatment returned the expression of ~93% of DEPs to drug-free levels for both human serum and EGF. Gene ontology enrichment and OncoboxPD pathway activation level analysis showed that lapatinib addition influenced mostly common functional processes revealed in RNA- and protein-based assays. However, a specific feature was observed at the proteome level: addition of lapatinib increased the expression of proteins associated with mitochondrial function and cellular respiration. This feature was not observed when using RNA sequencing data for the same experiments. However, it is consistent with the results of the resazurin test, which showed a 1.8-fold increase in SK-BR-3 cellular respiration upon exposure to lapatinib. Thus, we conclude that enhanced cellular respiration is a novel additional mechanism of action of lapatinib on HER2-positive cancer cells.
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Project description:Grb2 is a small SH2-SH3 adaptor molecule that interacts with activated tyrosine kinase receptors (RTKs), providing a crucial link towards downstream activation of pro-proliferative and pro-survival ERK and Akt signaling pathways. Ret and FGFR2, two RTKs that interact with Grb2, play important roles in ureteric branching and the proper establishment of the renal collecting duct system, but it is unclear whether Grb2 is required in this process. In this study, we selectively ablated a conditional floxed allele of the Grb2 gene within the ureteric epithelial lineage in mice and demonstrate that Grb2 signaling is essentially required for proper collecting duct development. Ureteric Grb2 deficiency results in perinatal lethality and severe renal hypodysplasia closely reminiscent of the rudimentary kidney phenotypes observed in Ret-null mutant mice. Grb2 loss attenuates ERK and Akt activation in the ureteric epithelia resulting in pronounced impairment of ureteric branching. Gene expression analysis reveals that Grb2 deficiency results in defective induction of genes implicated in both ureteric branching and reciprocal mesenchymal metanephric induction. Our findings therefore strongly indicate that Grb2 is a physiologically-relevant major RTK signaling relay partner that promotes renal branching morphogenesis and the proper development of the collecting duct system and the urogenital tract. Microarray was used to profile and compare the transcriptomes of developing kidneys of E14.5 Grb2 conditional knockout (ureteric-bud specific) and wild-type embryos
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Project description:Forkhead box protein A1 (FOXA1) has been shown to have critical functions in prostate and ER alpha positive breast cancer. As a pioneering transcriptional factor, FOXA1 regulates DNA accessibility for the androgen receptor in prostate and the estrogen receptor alpha in ER positive breast cancer, respectively. FOXA1 is also expressed in human epidermal growth factor receptor-2 (HER2/ErbB2) positive breast cancers, but its functions in HER2 positive breast cancer are unclear. The loss of FOXA1 results in a decrease in the viability of HER2 positive and HER2 amplified cell lines suggesting that FOXA1 may have an important role in HER2 positive breast cancers. In this report, we examined patient-derived single-cell RNA sequencing and spatial transcriptomics data and demonstrated that FOXA1 is co-expressed with ErbB2 in HER2 positive breast cancers. Knocking down FOXA1 expression led to the reduction of HER2 expression and signaling. Chromatin Immunoprecipitation Sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) identified FOXA1 binding motifs in the ErbB2 promoter and regulatory element regions, which controlled ErbB2 gene expression. Interestingly, the knockdown of FOXA1 increased Epithelial Mesenchymal Transition (EMT) signaling and inhibited luminal tumor differentiation. Furthermore, FOXA1 and TRPS1 regulated TEAD/YAP-TAZ activity. Taken together, our data demonstrate that FOXA1 is required for HER2 expression and luminal identity in HER2+ breast cancer.
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Project description:Forkhead box protein A1 (FOXA1) has been shown to have critical functions in prostate and ER alpha positive breast cancer. As a pioneering transcriptional factor, FOXA1 regulates DNA accessibility for the androgen receptor in prostate and the estrogen receptor alpha in ER positive breast cancer, respectively. FOXA1 is also expressed in human epidermal growth factor receptor-2 (HER2/ErbB2) positive breast cancers, but its functions in HER2 positive breast cancer are unclear. The loss of FOXA1 results in a decrease in the viability of HER2 positive and HER2 amplified cell lines suggesting that FOXA1 may have an important role in HER2 positive breast cancers. In this report, we examined patient-derived single-cell RNA sequencing and spatial transcriptomics data and demonstrated that FOXA1 is co-expressed with ErbB2 in HER2 positive breast cancers. Knocking down FOXA1 expression led to the reduction of HER2 expression and signaling. Chromatin Immunoprecipitation Sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) identified FOXA1 binding motifs in the ErbB2 promoter and regulatory element regions, which controlled ErbB2 gene expression. Interestingly, the knockdown of FOXA1 increased Epithelial Mesenchymal Transition (EMT) signaling and inhibited luminal tumor differentiation. Furthermore, FOXA1 and TRPS1 regulated TEAD/YAP-TAZ activity. Taken together, our data demonstrate that FOXA1 is required for HER2 expression and luminal identity in HER2+ breast cancer.
2024-09-01 | GSE267920 | GEO
Project description:Forkhead box protein A1 (FOXA1) has been shown to have critical functions in prostate and ER alpha positive breast cancer. As a pioneering transcriptional factor, FOXA1 regulates DNA accessibility for the androgen receptor in prostate and the estrogen receptor alpha in ER positive breast cancer, respectively. FOXA1 is also expressed in human epidermal growth factor receptor-2 (HER2/ErbB2) positive breast cancers, but its functions in HER2 positive breast cancer are unclear. The loss of FOXA1 results in a decrease in the viability of HER2 positive and HER2 amplified cell lines suggesting that FOXA1 may have an important role in HER2 positive breast cancers. In this report, we examined patient-derived single-cell RNA sequencing and spatial transcriptomics data and demonstrated that FOXA1 is co-expressed with ErbB2 in HER2 positive breast cancers. Knocking down FOXA1 expression led to the reduction of HER2 expression and signaling. Chromatin Immunoprecipitation Sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) identified FOXA1 binding motifs in the ErbB2 promoter and regulatory element regions, which controlled ErbB2 gene expression. Interestingly, the knockdown of FOXA1 increased Epithelial Mesenchymal Transition (EMT) signaling and inhibited luminal tumor differentiation. Furthermore, FOXA1 and TRPS1 regulated TEAD/YAP-TAZ activity. Taken together, our data demonstrate that FOXA1 is required for HER2 expression and luminal identity in HER2+ breast cancer.
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