C/EBPβ regulates the JAK/STAT signaling pathway in triple-negative breast cancer.
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ABSTRACT:
SUBMITTER: Wang S
PROVIDER: S-EPMC8016132 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Due to the lack of effective therapies and poor prognosis in TNBC (triple-negative breast cancer) patients, there is a strong need to develop effective novel targeted therapies for this subtype of breast cancer. Inhibition of heat shock protein 90 (HSP90), a conserved molecular chaperone that is involved in the regulation of oncogenic client proteins, has shown to be a promising therapeutic approach for TNBC. However, both intrinsic and acquired resistance to HSP90 inhibitors (HSP90i) limits their effectiveness in cancer patients. METHODS:We developed models of acquired resistance to HSP90i by prolonged exposure of TNBC cells to HSP90i (ganetespib) in vitro. Whole transcriptome profiling and a 328-compound bioactive small molecule screen were performed on these cells to identify the molecular basis of acquired resistance to HSP90i and potential therapeutic approaches to overcome resistance. RESULTS:Among a panel of seven TNBC cell lines, the most sensitive cell line (Hs578T) to HSP90i was selected as an in vitro model to investigate acquired resistance to HSP90i. Two independent HSP90i-resistant clones were successfully isolated which both showed absence of client proteins degradation, apoptosis induction and G2/M cell cycle arrest after treatment with HSP90i. Gene expression profiling and pathway enrichment analysis demonstrate significant activation of the survival JAK-STAT signalling pathway in both HSP90i-resistant clones, possibly through IL6 autocrine signalling. A bioactive small molecule screen also demonstrated that the HSP90i-resistant clones showed selective sensitivity to JAK2 inhibition. Inhibition of JAK and HSP90 caused higher induction of apoptosis, despite prior acquired resistance to HSP90i. CONCLUSIONS:Acquired resistance to HSP90i in TNBC cells is associated with an upregulated JAK-STAT signalling pathway. A combined inhibition of the JAK-STAT signalling pathway and HSP90 could overcome this resistance. The benefits of the combined therapy could be explored further for the development of effective targeted therapy in TNBC patients.
| S-EPMC6345040 | biostudies-literature
Project description:Dysregulated JAK/STAT signaling has been implicated in breast cancer metastasis, which is associated with high relapse risks. However, mechanisms underlying JAK/STAT signaling-mediated breast tumorigenesis are poorly understood. Here, we showed that GRAMD1B expression is upregulated on IL-6 but downregulated upon treatment with the JAK2 inhibitor AG490 in the breast cancer MDA-MB-231 cells. Notably, Gramd1b knockdown caused morphological changes of the cells, characterized by the formation of membrane ruffling and protrusions, implicating its role in cell migration. Consistently, GRAMD1B inhibition significantly enhanced cell migration, with an increase in the levels of the Rho family of GTPases. We also found that Gramd1b knockdown-mediated pro-migratory phenotype is associated with JAK2/STAT3 and Akt activation, and that JAK2 or Akt inhibition efficiently suppresses the phenotype. Interestingly, AG490 dose-dependently increased p-Akt levels, and our epistasis analysis suggested that the effect of JAK/STAT inhibition on p-Akt is via the regulation of GRAMD1B expression. Taken together, our results suggest that GRAMD1B is a key signaling molecule that functions to inhibit cell migration in breast cancer by negating both JAK/STAT and Akt signaling, providing the foundation for its development as a novel biomarker in breast cancer.
| S-EPMC6015000 | biostudies-literature
Project description:Protein arginine methyltransferases (PRMTs) modulate diverse cellular processes, including stress responses. The present study explored the role of Prmt7 in protecting against menopause-associated cardiomyopathy. Mice with cardiac-specific Prmt7 ablation (cKO) exhibited sex-specific cardiomyopathy. Male cKO mice exhibited impaired cardiac function, myocardial hypertrophy, and interstitial fibrosis associated with increased oxidative stress. Interestingly, female cKO mice predominantly exhibited comparable phenotypes only after menopause or ovariectomy (OVX). Prmt7 inhibition in cardiomyocytes exacerbated doxorubicin (DOX)-induced oxidative stress and DNA double-strand breaks, along with apoptosis-related protein expression. Treatment with 17β-estradiol (E2) attenuated the DOX-induced decrease in Prmt7 expression in cardiomyocytes, and Prmt7 depletion abrogated the protective effect of E2 against DOX-induced cardiotoxicity. Transcriptome analysis of ovariectomized wild-type (WT) or cKO hearts and mechanical analysis of Prmt7-deficient cardiomyocytes demonstrated that Prmt7 is required for the control of the JAK/STAT signaling pathway by regulating the expression of suppressor of cytokine signaling 3 (Socs3), which is a negative feedback inhibitor of the JAK/STAT signaling pathway. These data indicate that Prmt7 has a sex-specific cardioprotective effect by regulating the JAK/STAT signaling pathway and, ultimately, may be a potential therapeutic tool for heart failure treatment depending on sex.
| S-EPMC10985114 | biostudies-literature
Project description:PurposeTo investigate the role of EGFR and STAT3 in breast cancer development and progression.MethodsThrough bioinformatics analysis differently expressed genes (DEGs) including EGFR and STAT3 were identified in breast cancer tissue. QRT-PCR and Western blot analysis were used to investigate EGFR and STAT3 levels in breast cancer tissues and cells. The influence of EGFR and STAT3 on the breast cancer cell proliferation (CCK-8 assay, clone formation assays), migration (wound healing assays) and invasion (transwell assays) were investigated. The influence of EGFR on breast cancer in vivo was examined by Nude mouse transplantation tumor experiments and immunohistochemistry (IHC) staining. The effects of EGFR on breast cancer signaling were assessed via Western blot.ResultsBoth EGFR and p-STAT3 were up-regulated in breast cancer tissues and cell lines. EGFR expression was positively associated with p-STAT3. Moreover, EGFR and p-STAT3 activity enhanced the proliferation and invasion of tumor cells. Breast cancer cell growth was dramatically inhibited by EGFR silencing in vivo.ConclusionEGFR promotes breast cancer progression via STAT3 phosphorylation and JAK/STAT3 signaling.
| S-EPMC6996555 | biostudies-literature
Project description:Conserved from humans to Drosophila, the Janus kinase/signal transducer and activators of transcription (JAK/STAT) signaling cascade is essential for multiple developmental and homeostatic processes, with regulatory molecules controlling pathway activity also highly conserved. We characterize the Drosophila JAK/STAT pathway regulator SOCS36E and show that it functions via two independent mechanisms. First, we show that Drosophila Elongin B/C and Cullin-5 act via the SOCS-box of SOCS36E to reduce pathway activity specifically in response to ligand stimulation--a process that involves endocytic trafficking and lysosomal degradation of the Domeless (Dome) receptor. Second, SOCS36E also suppresses both stimulated and basal pathway activity via an Elongin/Cullin-independent mechanism that is mediated by the N-terminus of SOCS36E, which is required for the physical interaction of SOCS36E with Dome. Although some human SOCS proteins contain N-terminal kinase-inhibitory domains, we do not identify such a region in SOCS36E and propose a model wherein the N-terminal of SOCS36E blocks access to tyrosine residues in Dome. Our biochemical analysis of a SOCS-family regulator from a lower organism highlights the fundamental conserved roles played by regulatory mechanisms in signal transduction.
| S-EPMC3771960 | biostudies-literature
Project description:Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer.?.
| S-EPMC6348154 | biostudies-literature
Project description:The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), suppressors of cytokine signaling (SOCS)1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population-based case-control studies (colon cancer n?=?1555 cases, 1,956 controls; rectal cancer n?=?754 cases, 959 controls). JAK2, SOCS2, STAT1, STAT3, STAT5A, STAT5B, and STAT6 were associated with colon cancer; STAT3, STAT4, STAT6, and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT-signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1, STAT4, and TYK2 with estrogen status; and JAK2, STAT2, STAT4, STAT5A, STAT5B, and STAT6 with smoking status and colon cancer risk; JAK2, STAT6, and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2, SOCS1, STAT3, STAT5, and TYK2 were associated with colon cancer survival (hazard rate ratio (HRR) of 3.3 95% CI 2.01,5.42 for high mutational load). JAK2, SOCS1, STAT1, STAT4, and TYK2 were associated with rectal cancer survival (HRR 2.80 95% CI 1.63,4.80). These data support the importance of the JAK/STAT-signaling pathway in colorectal cancer and suggest targets for intervention.
| S-EPMC3430812 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapeutics. The luminal androgen receptor (LAR) subtype constitutes 15% of TNBC and is enriched for androgen receptor (AR) and AR target genes. Here, we show that a cohort of TNBC not only expresses AR at a much higher rate (∼80%) but also expresses AR splice variants (AR-SVs) (∼20%), further subclassifying LAR-TNBC. Higher AR and AR-SV expression and corresponding aggressive phenotypes are observed predominantly in specimens obtained from African American women. LAR TNBC specimens are enriched for interferon, Janus kinase (JAK)-signal activator and transducer (STAT), and androgen signaling pathways, which are exclusive to AR-expressing epithelial cancer cells. AR- and AR-SV-expressing TNBC cell proliferation and xenograft and patient-tumor explant growth are inhibited by AR N-terminal domain-binding selective AR degrader or by a JAK inhibitor. Biochemical analysis suggests that STAT1 is an AR coactivator. Collectively, our work identifies pharmacologically targetable TNBC subtypes and identifies growth-promoting interaction between AR and JAK-STAT signaling.
| S-EPMC10872270 | biostudies-literature
Project description:Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression.
| S-EPMC10573125 | biostudies-literature
Project description:Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.SignificanceChemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
| S-EPMC9845989 | biostudies-literature