Molecular Cancer Research最新文献

{"title":"NAP1L1 Promotes Endometrial Cancer Progression via EP300-Mediated DDX5 Promoter Acetylation.","authors":"Xiangfei Zhu, Yishan Li, Zhiying Shao, Xiaoyuan Lu, Youguo Chen","doi":"10.1158/1541-7786.MCR-23-0871","DOIUrl":"10.1158/1541-7786.MCR-23-0871","url":null,"abstract":"<p><p>Endometrial cancer is one of the predominant tumors of the female reproductive system. In this current study, we investigated the functions and related mechanisms of nucleosome assembly protein 1 like 1 (NAP1L1)/ DEAD-box helicase 5 (DDX5) in endometrial cancer. This retrospective study analyzed the medical records of patients with endometrial cancer, collected tissue samples for NAP1L1 and DDX5 staining, and conducted survival analysis using the Kaplan-Meier method. To evaluate the impact of NAP1L1 and/or DDX5 on cellular processes in endometrial cancer cells, several techniques were employed. These included Cell Counting Kit-8 assay, wound healing assay, Transwell assay, as well as overexpression or knockdown of target gene expression. Additionally, chromatin immunoprecipitation, dual luciferase reporter gene, and coimmunoprecipitation (Co-IP) assay were utilized to confirm the interaction between NAP1L1, E1A-binding protein p300 (EP300), and DDX5. Furthermore, qRT-PCR, Western blot, and Co-IP assay were performed to analyze the modulation of NAP1L1/DDX5 in Wnt/β-catenin. NAP1L1 and DDX5 expression were upregulated in endometrial cancer tissues, and correlated with poor prognosis. NAP1L1/DDX5 promoted endometrial cancer cell proliferation, migration, and invasion. NAP1L1 promotes acetylation and transcription by recruiting EP300 to the DDX5 promoter. DDX5 could activate Wnt/β-catenin signal by binding to β-catenin. In animal models, knockdown of NAP1L1 inhibits endometrial cancer tumor growth and lung metastasis. To sum up, our study demonstrated that NAP1L1 promoted the malignant phenotypes of endometrial cancer cells via recruiting EP300 to promote DDX5 acetylation, thus activating the Wnt/β-catenin signaling pathway. Implications: Our research findings indicate that targeting the NAP1L1/EP300/DX5 axis might be a new potential treatment option for endometrial cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1011-1021"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141492801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNA-WAL Promotes Triple-Negative Breast Cancer Aggression by Inducing β-Catenin Nuclear Translocation.","authors":"Hongyan Huang, Haiyun Jin, Rong Lei, Zhanghai He, Shishi He, Jiewen Chen, Phei E Saw, Zhu Qiu, Guosheng Ren, Yan Nie","doi":"10.1158/1541-7786.MCR-23-0334","DOIUrl":"10.1158/1541-7786.MCR-23-0334","url":null,"abstract":"<p><p>Because of its insensitivity to existing radiotherapy, namely, chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/β-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated Wnt/β-catenin pathway of TNBC tissues, lnc-WAL (Wnt/β-catenin-associated lncRNA; WAL) was selected as the top upregulated lncRNA in Wnt/β-catenin pathway activation compared with the inactivation group. RNA immunoprecipitation sequencing was used to compare the β-catenin and IgG groups, in which lnc-WAL could interact with β-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted epithelial-mesenchymal transition, the proliferation, migration, and invasion of breast cancer stem cells and TNBC cells. Mechanistically, lnc-WAL inhibited β-catenin protein degradation via AXIN-mediated phosphorylation at serine 45. Subsequently, β-catenin accumulated in the nucleus and activated the target genes. Importantly, Wnt/β-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/AXIN/β-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/β-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for patients with TNBC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1036-1050"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hnRNPAB Promotes Pancreatic Ductal Adenocarcinoma Extravasation and Liver Metastasis by Stabilizing MYC mRNA.","authors":"Ke Lei, Mingyue Sun, Xianghan Chen, Jia Wang, Xiaolan Liu, Ying Ning, Shuai Ping, Ruining Gong, Yu Zhang, Gong Qing, Chenyang Zhao, He Ren","doi":"10.1158/1541-7786.MCR-24-0110","DOIUrl":"10.1158/1541-7786.MCR-24-0110","url":null,"abstract":"<p><p>Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) is considered a cancer-promoting heterogeneous nuclear ribonucleoprotein in many cancers, but its function in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. hnRNPAB was highly expressed in PDAC tissues compared with normal pancreatic tissues, and high expression of hnRNPAB was associated with poor overall survival and recurrence-free survival in patients with PDAC. hnRNPAB promotes migration and invasion of PDAC cells in vitro. In xenograft tumor mouse models, hnRNPAB deprivation significantly attenuated liver metastasis. hnRNPAB mRNA and protein levels are positively associated with MYC in PDAC cells. Mechanistically, hnRNPAB bound to MYC mRNA and prolonged its half-life. hnRNPAB induced PDAC cells to secrete CXCL8 via MYC, which promoted neutrophil recruitment and facilitated tumor cells entrancing into the hepatic parenchyma. These findings point to a novel regulatory mechanism via which hnRNPAB promotes PDAC metastasis. Implications: hnRNPAB participates in the posttranscriptional regulation of the oncogene MYC by binding and stabilizing MYC mRNA, thereby promoting liver metastasis in PDAC.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"1022-1035"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin Ligase TRIM22 Inhibits Ovarian Cancer Malignancy via TCF4 Degradation.","authors":"Tao Tao, Yongqi Zhang, Chunyan Guan, Shuxiang Wang, Xiaoli Liu, Min Wang","doi":"10.1158/1541-7786.MCR-23-0962","DOIUrl":"10.1158/1541-7786.MCR-23-0962","url":null,"abstract":"<p><p>Ovarian cancer is one of the most common malignancies in women. Tripartite motif-containing protein 22 (TRIM22) plays an important role in the initiation and progression of malignant tumors. Similarly, the transcription factor 4 (TCF4) is an essential factor involved in the initiation and progression of many tumors. However, it is still unclear whether TRIM22 can affect TCF4 in ovarian cancer. Therefore, this study aims to investigate the mechanism related to TRIM22 and TCF4 in ovarian cancer. TRIM22 protein and mRNA levels were analyzed in samples from clinical and cell lines. The effects of TRIM22 knockdown and overexpression on cell proliferation, colony formation, migration, invasion, and related biomarkers were evaluated. In addition, the role of ubiquitination-mediated degradation of TCF4 was investigated by qRT-PCR and Western blotting. The association between TRIM22 and TCF4 was evaluated by Western blotting, coimmunoprecipitation, proliferation, colony formation, invasion, migration, and related biomarkers. The results showed that the expression of TRIM22 was minimal in ovarian cancer tissues. Furthermore, upregulation of TRIM22 significantly inhibited ovarian cancer cell proliferation, colony formation, migration, and invasion. In addition, TRIM22 was observed to regulate the degradation of TCF4 through the ubiquitination pathway. TCF4 can reverse the effects of TRIM22 on proliferation, colony formation, migration, and invasion in ovarian cancer cells. TRIM22-mediated ubiquitination of TCF4 at K48 is facilitated by the RING domain. Implications: In conclusion, ubiquitination of TCF4 protein in ovarian cancer is regulated by TRIM22, which has the potential to limit the proliferation, migration, and invasion of ovarian cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"943-956"},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141262339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-Binding Protein Lin28B Promotes Chronic Myeloid Leukemia Blast Crisis by Transcriptionally Upregulating miR-181d.","authors":"Minran Zhou, Xiaolin Yin, Lu Zhang, Zelong Cui, Xinwen Jiang, Qingli Ji, Sai Ma, Chunyan Chen","doi":"10.1158/1541-7786.MCR-23-0928","DOIUrl":"10.1158/1541-7786.MCR-23-0928","url":null,"abstract":"<p><p>The blast crisis (BC) of chronic myeloid leukemia (CML) has poor efficacy against existing treatments and extremely short survival. However, the molecular mechanism of CML-chronic phase (CP) transformation to CML-BC is not yet fully understood. Here, we show that Lin28B, an RNA-binding protein, acted as an activator enhancing the transformation to CML-BC by mediating excessive cell proliferation. The level of Lin28B expression was apparently elevated in patients with CML-BC compared with newly diagnosed patients with CML-CP. The overexpression of Lin28B promoted the proliferation of leukemia cells. Mechanistically, we identified Lin28B as a DNA-binding protein by binding to the promoter region of miR-181d and upregulating its expression, which inhibited the expression of programmed cell death 4 (PDCD4) by binding to the PDCD4 3'UTR region, thereby enhancing the proliferation of CML cells. Overall, the \"Lin28B-miR-181d-PDCD4\" regulatory axis promoted CML blast crisis. Implications: Our findings highlight the oncogenic role of Lin28B in CML blast crisis, acting as a DNA-binding protein that transcriptionally upregulates miR-181d expression.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"932-942"},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Complex Regulation of Cytokinesis upon Abscission Checkpoint Activation.","authors":"Paulius Gibieža, Vilma Petrikaitė","doi":"10.1158/1541-7786.MCR-24-0365","DOIUrl":"10.1158/1541-7786.MCR-24-0365","url":null,"abstract":"<p><p>Cytokinetic abscission is a crucial process that guides the separation of daughter cells at the end of each cell division. This process involves the cleavage of the intercellular bridge, which connects the newly formed daughter cells. Over the years, researchers have identified several cellular contributors and intracellular processes that influence the spatial and temporal distribution of the cytoskeleton during cytokinetic abscission. This review presents the most important scientific discoveries that allow activation of the abscission checkpoint, ensuring a smooth and successful separation of a single cell into two cells during cell division. Here, we describe different factors, such as abscission checkpoint, ICB tension, nuclear pore defects, DNA replication stress, chromosomal stability, and midbody proteins, which play a role in the regulation and correct timing of cytokinetic abscission. Furthermore, we explore the downsides associated with the dysregulation of abscission, including its negative impact on cells and the potential to induce tumor formation in humans. Finally, we propose a novel factor for improving cancer therapy and give future perspectives in this research field.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"909-919"},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate Induces Tumor Progression via LAR Motif-Dependent Yin-Yang 1 Degradation.","authors":"Shujuan Du, Xiaoting Chen, Xiao Han, Yuyan Wang, Dan Yu, Ying Li, Caixia Zhu, Yin Tong, Shujun Gao, Junwen Wang, Fang Wei, Qiliang Cai","doi":"10.1158/1541-7786.MCR-23-0583","DOIUrl":"10.1158/1541-7786.MCR-23-0583","url":null,"abstract":"<p><p>The metabolic reprogramming of aerobic glycolysis contributes to tumorigenesis. High plasma lactate is a critical regulator in the development of many human malignancies; however, the underlying molecular mechanisms of cancer progression in response to lactate (LA) remain elusive. Here, we show that the reduction of Yin-Yang 1 (YY1) expression correlated with high LA commonly occurs in various cancer cell types, including B-lymphoma and cervical cancer. Mechanistically, LA induces YY1 nuclear export and degradation via HSP70-mediated autophagy adjacent to mitochondria in a histidine (His)-rich LA-responsive (LAR) motif-dependent manner. The mutation of the LAR motif blocks LA-mediated YY1 cytoplasmic accumulation and in turn enhances cell apoptosis. Furthermore, low expression of YY1 promotes colony formation, invasion, angiogenesis, and growth of cancer cells in response to LA in vitro and in vivo using a murine xenograft model. Taken together, our findings reveal a key LAR element and may serve as therapeutic target for intervening cancer progression. Implications: We have shown that lactate can induce YY1 degradation via its His-rich LAR motif and low expression of YY1 promotes cancer cell progression in response to lactate, leading to better prediction of YY1 targeting therapy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"957-972"},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141420015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAPRT Silencing in FH-Deficient Renal Cell Carcinoma Confers Therapeutic Vulnerabilities via NAD+ Depletion.","authors":"Katelyn J Noronha, Karlie N Lucas, Sateja Paradkar, Joseph Edmonds, Sam Friedman, Matthew A Murray, Samantha Liu, Dipti P Sajed, Chana Sachs, Josh Spurrier, Mitch Raponi, Jiayu Liang, Hao Zeng, Ranjini K Sundaram, Brian Shuch, Juan C Vasquez, Ranjit S Bindra","doi":"10.1158/1541-7786.MCR-23-1003","DOIUrl":"10.1158/1541-7786.MCR-23-1003","url":null,"abstract":"<p><p>Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. Loss of FH leads to accumulation of fumarate, an oncometabolite that disrupts multiple cellular processes and drives tumor progression. High levels of fumarate inhibit alpha ketoglutarate-dependent dioxygenases, including the ten-eleven translocation (TET) enzymes, and can lead to global DNA hypermethylation. Here, we report patterns of hypermethylation in FH-mutant cell lines and tumor samples are associated with the silencing of nicotinate phosphoribosyl transferase (NAPRT), a rate-limiting enzyme in the Preiss-Handler pathway of NAD+ biosynthesis, in a subset of HLRCC cases. NAPRT is hypermethylated at a CpG island in the promoter in cell line models and patient samples, resulting in loss of NAPRT expression. We find that FH-deficient RCC models with loss of NAPRT expression, as well as other oncometabolite-producing cancer models that silence NAPRT, are extremely sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTi). NAPRT silencing was also associated with synergistic tumor cell killing with PARP inhibitors and NAMPTis, which was associated with effects on PAR-mediated DNA repair. Overall, our findings indicate that NAPRT silencing can be targeted in oncometabolite-producing cancers and elucidates how oncometabolite-associated hypermethylation can impact diverse cellular processes and lead to therapeutically relevant vulnerabilities in cancer cells. Implications: NAPRT is a novel biomarker for targeting NAD+ metabolism in FH-deficient HLRCCs with NAMPTis alone and targeting DNA repair processes with the combination of NAMPTis and PARP inhibitors.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"973-988"},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Wnt Signaling Pathway Aberrations in Metastatic Prostate Cancer.","authors":"Sharon H Choi, Elizabeth Pan, Andrew Elliott, Himisha Beltran, Justine Panian, Christina Jamieson, Aditya Bagrodia, Brent Rose, Daniel Herchenhorn, Elisabeth Heath, Chadi Nabhan, Emmanuel S Antonarakis, Rana R McKay","doi":"10.1158/1541-7786.MCR-24-0395","DOIUrl":"10.1158/1541-7786.MCR-24-0395","url":null,"abstract":"<p><p>Wnt (wingless-type) signaling pathway (WSP) alterations have been identified in patients with prostate cancer and are implicated in disease progression and hormonal resistance. In this study, we utilized a multi-institutional dataset to characterize molecular alterations in the canonical and noncanonical WSPs in prostate cancer. Patients with prostate cancer who underwent tissue-based genomic sequencing were investigated. Tumors with somatic activating mutations in CTNNB1 or RSPO2 or inactivating mutations in either APC or RNF43 were characterized as having aberrant canonical Wnt signaling (WSP-activated). Overall survival analyses were restricted to microsatellite-stable (MSS) tumors lacking RNF43 G659fs* mutations. We also investigated noncanonical WSP by evaluation of ROR1, ROR2, and WNT5 in WSP-activated versus WSP wild-type (WSP-WT) tumors. Of 4,138 prostate cancer samples, 3,684 were MSS. Among MSS tumors, 42.4% were from metastatic sites, of which 19.1% were WSP activated, and 57.6% were from the prostate, of which 10.1% were WSP activated. WSP-activated tumors were more prevalent in metastatic sites than in primary prostate cancer. WSP-activated prostate cancer exhibited more SPOP mutations and higher expression of canonical WSP activators than WSP-WT tumors. ROR1 gene expression was elevated in WSP-activated tumors from both primary and metastatic sites. M2 macrophages predominated the tumor microenvironment in WSP-activated tumors. There was no significant difference in overall survival between patients with WSP-activated and WSP-WT prostate cancer. WSP-activated prostate cancer demonstrated a more immunosuppressed tumor microenvironment and a pronounced upregulation of ROR1 gene expression, underscoring its potential involvement in the crosstalk between canonical and noncanonical WSPs. Implications: Our findings may provide a rationale for developing novel therapeutic strategies targeting Wnt-activated prostate cancer.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"920-931"},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"c-Myc, AKT, Hsc70, and the T-Box Transcription Factor TBX3 Form an Important Oncogenic Signaling Axis in Breast Cancer","authors":"Stephanie M. Ncube, ArulJothi Nagarajan, Dirk Lang, Musalula Sinkala, Carly A. Burmeister, Karabo Serala, Jonathan Blackburn, Sharon Prince","doi":"10.1158/1541-7786.mcr-23-1031","DOIUrl":"https://doi.org/10.1158/1541-7786.mcr-23-1031","url":null,"abstract":"Breast cancer is the second leading cause of death in women globally, and it remains a health burden due to poor therapy response, cancer cell drug resistance, and the debilitating side effects associated with most therapies. One approach to addressing the need to improve breast cancer therapies has been to elucidate the mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. The T-box transcription factor, TBX3, is upregulated in breast cancer, in which it contributes to important oncogenic processes, and it has been validated as a potential therapeutic target. Here, we investigated the molecular mechanisms that upregulate TBX3 in breast cancer, and we show that it involves transcriptional activation by c-Myc, post-translational modification by AKT1 and AKT3, and interaction with the molecular chaperone Hsc70. Together, the results from this study provide evidence that c-Myc, AKT, Hsc70, and TBX3 form part of an important oncogenic pathway in breast cancer and thus reveal versatile ways of interfering with the oncogenic activity of TBX3 for the treatment of this neoplasm. Implications: Targeting the c-Myc/AKT/TBX3/Hsc70 signaling axis may be an effective treatment strategy for TBX3-driven breast cancer.","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":"21 1","pages":"OF1-OF13"},"PeriodicalIF":5.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142203090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}