bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–08–11
thirteen papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. IBSP Promotes Breast Cancer Bone Metastasis and Proliferation via BMP-SMAD Signaling Pathway.
  2. Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy.
  3. Hypoxia-inducible factor-1α can reverse the Adriamycin resistance of breast cancer adjuvant chemotherapy by upregulating transferrin receptor and activating ferroptosis.
  4. Characterization of SUSD3 as a novel prognostic biomarker and therapeutic target for breast cancer.
  5. TCF12-regulated GRB7 facilitates the HER2+ breast cancer progression by activating Notch1 signaling pathway.
  6. YWHAB is regulated by IRX5 and inhibits the migration and invasion of breast cancer cells.
  7. ERα Coregulator TRIM28 Promotes Breast Cancer Progression by Activating the AKT/GSK3β Pathway.
  8. Upregulated bone morphogenetic protein 8A (BMP8A) in triple negative breast cancer (TNBC) and its involvement in the bone metastasis.
  9. STC2 suppresses triple-negative breast cancer migration and invasion by inhibition on EMT and promotion on cell apoptosis.
  10. Targeting fatty acid oxidation enhances response to HER2-targeted therapy.
  11. EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth.
  12. PKCα Induced the Generation of Extracellular Vesicles in Activated Platelets to Promote Breast Cancer Metastasis.
  13. Oncogenic transcription factors instruct promoter-enhancer hubs in individual triple negative breast cancer cells.
  1. Cancer Rep (Hoboken). 2024 Aug;7(8): e2153
    IBSP Promotes Breast Cancer Bone Metastasis and Proliferation via BMP-SMAD Signaling Pathway.
    Wei Ding, Di Lv, Mengshen Wang, Dongsheng Pei.
       BACKGROUND: Integrin-Binding Sialoprotein (IBSP) has been implicated in tumor progression across various cancers. However, the specific role of IBSP in breast cancer remains underexplored. There is a need to investigate the mechanisms by which IBSP influences breast cancer progression and its potential as a therapeutic target.
    AIMS: This study aims to elucidate the role of IBSP in breast cancer, particularly its impact on tumor progression and its relationship with prognosis. We also seek to understand the underlying mechanisms, including the involvement of the BMP-SMAD signaling pathway, and to explore the potential of targeting IBSP for therapeutic interventions.
    METHODS AND RESULTS: Overexpression of IBSP in breast cancer cells led to increased migration and invasion, whereas IBSP interference reduced these behaviors, indicating its role in enhancing tumor progression. Differentially expressed genes were significantly enriched in the BMP-SMAD signaling pathway, a critical pathway for osteogenic differentiation. Transcription Factor Binding: Dual luciferase reporter assays demonstrated that SMAD4 specifically binds to the IBSP promoter, establishing a regulatory link between SMAD4 and IBSP expression. Silencing IBSP (si-IBSP) mitigated the effects of SMAD4-induced tumor proliferation, confirming that IBSP acts as a downstream target of SMAD4 in the BMP signaling pathway.
    CONCLUSION: Our study reveals that IBSP plays a significant role in breast cancer progression through the BMP-SMAD4 signaling pathway. Targeting IBSP could be a promising therapeutic strategy for breast cancer treatment. Further research into IBSP inhibitors may offer new avenues for improving treatment outcomes and managing breast cancer more effectively.
    Keywords:  IBSP; breast cancer; metastasis; proliferation
    DOI:  https://doi.org/10.1002/cnr2.2153
  2. Cancer Res. 2024 Aug 06.
    Natural Killer Cell Regulation of Breast Cancer Stem Cells Mediates Metastatic Dormancy.
    Grace G Bushnell, Deeksha Sharma, Henry C Wilmot, Michelle Zheng, Toluwaleke D Fashina, Chloe M Hutchens, Samuel Osipov, Monika Burness, Max S Wicha.
      Breast cancer patients with estrogen receptor positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display "stem like" properties (CSCs), which may be regulated by the immune system. To elucidate the role of the immune system in controlling dormancy and its escape, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. Three mouse breast cancer cell lines, PyMT, Met-1 and D2.0R, contained CSCs that displayed both short- and long-term metastatic dormancy in vivo, which was dependent on the host immune system. Each model was regulated by different components of the immune system. Natural killer (NK) cells were key for the metastatic dormancy phenotype in D2.0R cells. Quiescent D2.0R CSCs were resistant to NK cell cytotoxicity, while proliferative CSCs were sensitive. Resistance to NK cell cytotoxicity was mediated, in part, by expression of BACH1 and SOX2 transcription factors. Expression of STING and STING targets was decreased in quiescent CSCs, and the STING agonist MSA-2 enhanced NK cell killing. Collectively, these findings demonstrate the role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0030
  3. FASEB J. 2024 Aug 15. 38(15): e23876
    Hypoxia-inducible factor-1α can reverse the Adriamycin resistance of breast cancer adjuvant chemotherapy by upregulating transferrin receptor and activating ferroptosis.
    Xiaojie Yu, Qingqun Guo, Haojie Zhang, Xiaohong Wang, Yong Han, Zhenlin Yang.
      Breast cancer is a common malignant tumor in women. Ferroptosis, a programmed cell death pathway, is closely associated with breast cancer and its resistance. The transferrin receptor (TFRC) is a key factor in ferroptosis, playing a crucial role in intracellular iron accumulation and the occurrence of ferroptosis. This study investigates the influence and significance of TFRC and its upstream transcription factor hypoxia-inducible factor-1α (HIF1α) on the efficacy of neoadjuvant therapy in breast cancer. The differential gene obtained from clinical samples through genetic sequencing is TFRC. Bioinformatics analysis revealed that TFRC expression in breast cancer was significantly greater in breast cancer tissues than in normal tissues, but significantly downregulated in Adriamycin (ADR)-resistant tissues. Iron-responsive element-binding protein 2 (IREB2) interacts with TFRC and participates in ferroptosis. HIF1α, an upstream transcription factor, positively regulates TFRC. Experimental results indicated higher levels of ferroptosis markers in breast cancer tissue than in normal tissue. In the TAC neoadjuvant regimen-sensitive group, iron ion (Fe2+) and malondialdehyde (MDA) levels were greater than those in the resistant group (all p < .05). Expression levels of TFRC, IREB2, FTH1, and HIF1α were higher in breast cancer tissue compared to normal tissue. Additionally, the expression of the TFRC protein in the TAC neoadjuvant regimen-sensitive group was significantly higher than that in the resistant group (all p < .05), while the difference in the level of expression of IREB2 and FTH1 between the sensitive and resistant groups was not significant (p > .05). The dual-luciferase assay revealed that HIF1α acts as an upstream transcription factor of TFRC (p < .05). Overexpression of HIF1α in ADR-resistant breast cancer cells increased TFRC, Fe2+, and MDA content. After ADR treatment, the cell survival rate decreased significantly, and ferroptosis could be reversed by the combined application of Fer-1 (all p < .05). In conclusion, ferroptosis and chemotherapy resistance are correlated in breast cancer. TFRC is a key regulatory factor influenced by HIF1α and is associated with chemotherapy resistance. Upregulating HIF1α in resistant cells may reverse resistance by activating ferroptosis through TFRC overexpression.
    Keywords:  Adriamycin resistance; HIF1α; TFRC; breast cancer; ferroptosis; transcription factor
    DOI:  https://doi.org/10.1096/fj.202401119R
  4. Clin Transl Oncol. 2024 Aug 06.
    Characterization of SUSD3 as a novel prognostic biomarker and therapeutic target for breast cancer.
    Yan-Ming Dong, Guo-Qiang Bao.
       BACKGROUND: Breast cancer (BC) remains a significant global health challenge, contributing substantially to cancer-related deaths worldwide. Its prevalence and associated death rates remain alarmingly high, highlighting the persistent public health burden. The objective of this study was to systematically examine the involvement of SUSD3 (Sushi Domain-Containing 3) in BC, highlighting its crucial role in the pathogenesis and progression of this disease.
    METHODS: BC-related gene microarray data, along with corresponding clinicopathological information, were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Leveraging TIMER and HPA databases, we conducted comparative analyses to evaluate SUSD3 expression in BC. We then analyzed the association between SUSD3 and clinical traits, as well as the prognostic value of SUSD3. SUSD3-related differential expression genes (DEGs) were sent for analysis utilizing GO, KEGG, and GSEA. We utilized SUSD3 mRNA expression to assess immune cells' scores in BC tissues calculated by single-sample enrichment analyses based on "CIBERSORT" R package. Drug sensitivity analysis was used to screen potential drugs sensitive to SUSD3. R software was used for statistical analyses and graphical representation of the data.
    RESULTS: Our findings confirmed a significant upregulation of SUSD3 expression in BC, which correlated with a favorable prognosis. Clinical correlation analysis further emphasized the strong association between SUSD3 expression and key clinical parameters like estrogen receptor (ER) status, progesterone receptor (PR) status, stage, and T classification in breast cancer. Univariate and multivariate Cox regression analyses showed that SUSD3 could be used as an independent prognostic factor for BC. Differentially expressed genes (DEGs) co-expressed with SUSD3 were significantly associated with various biological processes, such as the cell cycle, DNA replication, p53 signaling pathway, cancer-related pathways, and Wnt signaling pathway, as indicated by gene set enrichment analysis (GSEA). Furthermore, our analysis demonstrated that SUSD3 generally exhibited negative associations with immune modulators. Drug sensitivity analysis revealed positive correlations between SUSD3 and the efficacy of Fulvestrant, Raloxifene, and Fluphenazine.
    CONCLUSION: The research emphasizes the significance of SUSD3 as a potential marker for BC, providing insights into the underlying molecular mechanisms implicated in tumorigenesis. SUSD3 holds promise in helping the classification of breast cancer pathological groups, predicting prognosis, and facilitating targeted therapy.
    Keywords:  Bioinformatics; Biomarker; Breast cancer; Prognosis; SUSD3
    DOI:  https://doi.org/10.1007/s12094-024-03641-y
  5. J Transl Med. 2024 Aug 07. 22(1): 745
    TCF12-regulated GRB7 facilitates the HER2+ breast cancer progression by activating Notch1 signaling pathway.
    Gang Wang, Yuanli Wu, Yue Su, Na Qu, Bo Chen, Duanfang Zhou, Lie Yuan, Manjialan Yin, Mingpu Liu, Weiying Zhou.
       BACKGROUND: Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC), which accounts for approximately one-fifth of all BCs, are highly invasive with a high rate of recurrence and a poor prognosis. Several studies have shown that growth factor receptor-bound protein 7 (GRB7) might be a potential therapeutic target for tumor diagnosis and prognosis. Nevertheless, the role of GRB7 in HER2+ BC and its underlying mechanisms have not been fully elucidated. The aim of this study was to investigate the biological function and regulatory mechanism of GRB7 in HER2+ BC.
    METHODS: Bioinformatics analysis was performed using the TCGA, GEO and CancerSEA databases to evaluate the clinical significance of GRB7. RT quantitative PCR, western blot and immunofluorescence were conducted to assess the expression of GRB7 in BC cell lines and tissues. MTT, EdU, colony formation, wound healing, transwell, and xenograft assays were adopted to explore the biological function of GRB7 in HER2+ BC. RNA sequencing was performed to analyze the signaling pathways associated with GRB7 in SK-BR-3 cells after the cells were transfected with GRB7 siRNA. Chromatin immunoprecipitation analysis (ChIP) and luciferase reporter assay were employed to elucidate the potential molecular regulatory mechanisms of GRB7 in HER2+ BC.
    RESULTS: GRB7 was markedly upregulated and associated with poor prognosis in BC, especially in HER2+ BC. Overexpression of GRB7 increased the proliferation, migration, invasion, and colony formation of HER2+ BC cells, while depletion of GRB7 had the opposite effects in HER2+ BC cells and inhibited xenograft growth. ChIP-PCR and luciferase reporter assay revealed that TCF12 directly bound to the promoter of the GRB7 gene to promote its transcription. GRB7 facilitated HER2+ BC epithelial-mesenchymal transition (EMT) progression by interacting with Notch1 to activate Wnt/β-catenin pathways and other signaling (i.e., AKT, ERK). Moreover, forced GRB7 overexpression activated Wnt/β-catenin to promote EMT progression, and partially rescued the inhibition of HER2+ BC proliferation, migration and invasion induced by TCF12 silencing.
    CONCLUSIONS: Our work elucidates the oncogenic role of GRB7 in HER2+ BC, which could serve as a prognostic indicator and promising therapeutic target.
    Keywords:  Breast cancer; EMT; GRB7; HER2+ ; TCF12
    DOI:  https://doi.org/10.1186/s12967-024-05536-6
  6. Oncol Lett. 2024 Oct;28(4): 469
    YWHAB is regulated by IRX5 and inhibits the migration and invasion of breast cancer cells.
    Xuexia Geng, Jun Yuan, Wenjie Xu, Deng Zou, Yuxuan Sun, Jun Li.
      Highly metastatic and heterogeneous breast cancer affects the health of women worldwide. Abnormal expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB), also known as 14-3-3β, is associated with the tumorigenesis and progression of bladder cancer, lung cancer and hepatocellular carcinoma; however, to the best of our knowledge, the role of YWHAB in breast cancer remains unknown. In the present study, a dual luciferase assay demonstrated that the transcription factor iroquois homeobox 5 may regulate YWHAB expression by affecting the promoter sequence upstream of its transcription start site. Subsequently, it was demonstrated that overexpression of YWHAB did not affect proliferation, but did reduce the migration and invasion of MDA-MB-231 cells. Furthermore, knockdown of YWHAB promoted the migration and invasion of MCF7 cells. Transcriptomics analysis demonstrated that when YWHAB was overexpressed, 61 genes were differentially expressed, of which 43 genes were upregulated and 18 genes were downregulated. These differentially expressed genes (DEGs) were enriched in cancer-related pathways, such as 'TNF signaling pathway' [Kyoto Encyclopedia of Genes and Genomes (KEGG): map04688]. The pathway with the largest number of DEGs was 'Rheumatoid arthritis' (KEGG: map05323). Notably, YWHAB downregulated vimentin, which is a mesenchymal marker, thus suggesting that it may weaken the mesenchymal properties of cells. These findings indicate that YWHAB may be a potential therapeutic target in breast cancer and further work should be performed to assess its actions as a potential tumor suppressor.
    Keywords:  breast cancer; invasion; iroquois homeobox 5; migration; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β
    DOI:  https://doi.org/10.3892/ol.2024.14602
  7. Environ Toxicol. 2024 Aug 07.
    ERα Coregulator TRIM28 Promotes Breast Cancer Progression by Activating the AKT/GSK3β Pathway.
    Linlin Fu, Baodong Ma, Lan Zhang, Huikang Xu, Wei Chen, Di Wu, Feng Gao, Yanping Huo.
      Estrogen receptor α (ERα) promotes the growth and survival of ER-positive breast cancer (BC) cells. ER regulates ER expression target genes by directly binding to specific estrogen response elements, upon activation by estrogens. In this study, 106 proteins interacting with endogenous chromatin-bound ER in a BC cell line MCF7 were identified using the RIME method. The interactome data showed that the tripartite motif containing 28 (TRIM28) is the most significantly enriched ER-associated protein. This study provides evidence that TRIM28 expression improves ER transcriptional activity and promotes the BC cells proliferation, migration, and invasion of BC cells. The high expression of TRIM28 is associated with poor clinical outcomes in patients with ER-positive BC. Mechanistic experiments indicate that TRIM28 expression activates the AKT/GSK3β pathway. To conclude, TRIM28 acts as a regulatory protein of ER and AKT signaling; therefore, it can be a target for the therapeutic interventions of BC.
    Keywords:  AKT; TRIM28; breast cancer; estrogen receptor α
    DOI:  https://doi.org/10.1002/tox.24373
  8. Front Cell Dev Biol. 2024 ;12 1374269
    Upregulated bone morphogenetic protein 8A (BMP8A) in triple negative breast cancer (TNBC) and its involvement in the bone metastasis.
    Laijian Sui, Yizi Cong, Ming Liu, Xiangyi Liu, Yali Xu, Wen G Jiang, Lin Ye.
       Objective: The present study aimed to investigate the involvement of aberrant BMP8A expression in TNBC and bone metastasis.
    Methods: Aberrant expression of BMP8A in breast cancer was first determined by analyzing The Cancer Genome Atlas breast cancer cohort (TCGA-BRCA) and an immunohistochemical (IHC) staining of BMP8A in a breast cancer tissue microarray (TMA). Clinical relevance of deregulated BMP8A in breast cancer was assessed using Kaplan-Meier online analysis. The influence of BMP8A on cellular functions of two TNBC cell lines was assessed using in vitro assays. Conditional medium (CM) collected from the supernatant of hFOB cells and bone matrix extract (BME) was applied to mimic the bone micro-environment to evaluate the role played by BMP8A in bone metastasis. Correlations with both osteolytic and osteoblastic markers were evaluated in the TCGA-BRCA cohort. Expression of certain responsive genes was quantified in the BMP8A overexpression cell lines. Additionally, signal transduction through both Smad-dependent and independent pathways was evaluated using Western blot assay.
    Results: Compared to the adjacent normal tissues, BMP8A expression was significantly increased in primary tumors (p < 0.05) which was associated with shorter distant metastasis free survival (DMFS) in TNBC (p < 0.05). BMP8A was observed to enhance cell invasion and migration within TNBC cells. In the simulated bone milieu, both MDA-MB-231BMP8Aexp and BT549BMP8Aexp cells presented enhanced invasiveness. BMP8A level was strongly correlated with most osteolytic and osteoblastic markers, suggesting the potential involvement of BMP8A in bone metastasis in TNBC. Receptor activator of nuclear factor kappa-B ligand (RANKL) expression was significantly increased in BMP8A overexpressed triple-negative cell lines (MDA-MB-231 and BT549). Furthermore, enhanced phosphorylation of Smad3 and increased expression of epidermal growth factor receptor (EGFR) were observed in MDA-MB-231 cells overexpressing BMP8A.
    Conclusion: BMP8A was upregulated in TNBC which was associated with poorer DMFS. BMP8A overexpression enhanced the invasion and migration of TNBC cells. With a putative role in osteolytic bone metastasis in TNBC, BMP8A represents a promising candidate for further investigation into its therapeutic potential.
    Keywords:  BMP8A; bone metastasis; breast cancer; osteolytic; signal transduction
    DOI:  https://doi.org/10.3389/fcell.2024.1374269
  9. Discov Oncol. 2024 Aug 09. 15(1): 339
    STC2 suppresses triple-negative breast cancer migration and invasion by inhibition on EMT and promotion on cell apoptosis.
    Ruiwen Lei, Chaoling Yao, Renfeng Huang, Wanming Wu, Linyang Ou, Chuansheng Yang.
      To investigate the effects of higher cellular stanniocalcin 2 (STC2) on suppressing the migration and invasion but promoting the apoptosis of triple-negative breast cancer (TNBC). STC2 in TNBC and the para-carcinoma tissues were analyzed by immunohistochemistry (IHC), while the mRNA level was measured by qPCR. Over-expressing or silencing STC2 was established in MDA-MB-231 cells. Epithelial mesenchymal transition (EMT) related proteins, cell migration, invasion, proliferation and apoptosis were detected. MDA-MB-231 with over-expressing or silencing STC2 were injected into nude mice to formatting tumors, and then EMT related proteins were measured by IHC. Lower STC2 expressed in TNBC tissues than in the para-carcinoma tissues. Silencing STC2 promoted EMT of TNBC cell MDA-MB-231, as well as cell migration, invasion and proliferation, but suppressed MDA-MB-231 apoptosis, while over-expressing STC2 had the opposite results, which might be related to PKC/PI3K/AKT/mTOR pathway. STC2 was the protective gene in TNBC, by suppressing migration and invasion to inhibit MDA-MB-231 cell EMT but promote cell apoptosis, in order to suppress TNBC progression.
    Keywords:  Apoptosis; Invasion; MDA-MB-231; Migration; STC2; TNBC
    DOI:  https://doi.org/10.1007/s12672-024-01196-6
  10. Nat Commun. 2024 Aug 03. 15(1): 6587
    Targeting fatty acid oxidation enhances response to HER2-targeted therapy.
    Ipshita Nandi, Linjia Ji, Harvey W Smith, Daina Avizonis, Vasilios Papavasiliou, Cynthia Lavoie, Alain Pacis, Sherif Attalla, Virginie Sanguin-Gendreau, William J Muller.
      Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients.
    DOI:  https://doi.org/10.1038/s41467-024-50998-3
  11. Oncogene. 2024 Aug 07.
    EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth.
    Joshua Corbin, Xufen Yu, Jian Jin, Ling Cai, Gang Greg Wang.
      Breast cancer (BC) remains the second leading cause of cancer-related mortalities in women. Resistance to hormone therapies such as tamoxifen, an estrogen receptor (ER) inhibitor, is a major hurdle in the treatment of BC. Enhancer of zeste homolog 2 (EZH2), the methyltransferase component of the Polycomb repressive complex 2 (PRC2), has been implicated in tamoxifen resistance. Evidence suggests that EZH2 often functions noncanonically, in a methyltransferase-independent manner, as a transcription coactivator through interacting with oncogenic transcription factors. Unlike methyltransferase inhibitors, proteolysis targeting chimeras (PROTAC) can suppress both activating and repressive functions of EZH2. Here, we find that EZH2 PROTACs, MS177 and MS8815, effectively inhibited the growth of BC cells, including those with acquired tamoxifen resistance, to a much greater degree when compared to methyltransferase inhibitors. Mechanistically, EZH2 associates with forkhead box M1 (FOXM1) and binds to the promoters of FOXM1 target genes. EZH2 PROTACs induce degradation of both EZH2 and FOXM1, leading to reduced expression of target genes involved in cell cycle progression and tamoxifen resistance. Together, this study supports that EZH2-targeted PROTACs represent a promising avenue of research for the future treatment of BC, including in the setting of tamoxifen resistance.
    DOI:  https://doi.org/10.1038/s41388-024-03119-9
  12. Int J Biol Sci. 2024 ;20(10): 3956-3971
    PKCα Induced the Generation of Extracellular Vesicles in Activated Platelets to Promote Breast Cancer Metastasis.
    Jinghua Zhao, Huan Tian, Xiaona Zhao, Lan Lan, Huanhuan Liu, Yi Sun, Fengyan Yu.
      Platelet extracellular vesicles (PEVs) play an important role in tumor development. However, the mechanisms underlying their biogenesis have not been fully elucidated. Protein kinase Cα (PKCα) is an important regulator of platelet activation, but the effect of PKCα on EV generation is unclear. We used small-particle flow cytometry and found that the number of PEVs was increased in patients with breast cancer compared to those with benign breast disease. This was accompanied by increased levels of activated PKCα in breast cancer platelets. Treating platelets with the PKCα agonist phorbol 12-myristate 13-acetate (PMA) increased the phosphorylation PKCα and induced PEV production, while the PKCα inhibitor GÖ6976 showed the opposite effects. Notably, incubating platelets from patients with benign tumors with the culture supernatant of MDA-MB-231 cells induced PKCα phosphorylation in the platelets. Mass spectrometry and coimmunoprecipitation assays showed that Dynamin 2 (DNM2), a member of the guanosine-triphosphate-binding protein family, might cooperate with activated PKCα to regulate PEV production by breast cancer platelets. Similar results were observed in a mouse model of lung metastasis. In addition, PEVs were engulfed by breast cancer cells and promoted cancer cell migration and invasion via miR-1297 delivery. These findings suggested that PKCα cooperates with DNM2 to induce PEV generation, and PEV release might triggered by factors in the breast cancer environment.
    Keywords:  Breast Cancer; DNM2; PEVs; PKCα
    DOI:  https://doi.org/10.7150/ijbs.89822
  13. Sci Adv. 2024 Aug 09. 10(32): eadl4043
    Oncogenic transcription factors instruct promoter-enhancer hubs in individual triple negative breast cancer cells.
    Jingru Zhao, Yeqiao Zhou, Ilias Tzelepis, Noah G Burget, Junwei Shi, Robert B Faryabi.
      Sequencing-based mapping of ensemble pairwise interactions among regulatory elements support the existence of topological assemblies known as promoter-enhancer hubs or cliques in cancer. Yet, prevalence, regulators, and functions of promoter-enhancer hubs in individual cancer cells remain unclear. Here, we systematically integrated functional genomics, transcription factor screening, and optical mapping of promoter-enhancer interactions to identify key promoter-enhancer hubs, examine heterogeneity of their assembly, determine their regulators, and elucidate their role in gene expression control in individual triple negative breast cancer (TNBC) cells. Optical mapping of individual SOX9 and MYC alleles revealed the existence of frequent multiway interactions among promoters and enhancers within spatial hubs. Our single-allele studies further demonstrated that lineage-determining SOX9 and signaling-dependent NOTCH1 transcription factors compact MYC and SOX9 hubs. Together, our findings suggest that promoter-enhancer hubs are dynamic and heterogeneous topological assemblies, which are controlled by oncogenic transcription factors and facilitate subtype-restricted gene expression in cancer.
    DOI:  https://doi.org/10.1126/sciadv.adl4043
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