bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–11–24
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Down-regulation of ESRP2 inhibits breast cancer cell proliferation via inhibiting cyclinD1.
  2. MicroRNA-145-5p inhibits the tumorigenesis of breast cancer through SENP2-regulated ubiquitination of ERK2.
  3. Adipose stem cell exosomes, stimulated by pro-inflammatory factors, enhance immune evasion in triple-negative breast cancer by modulating the HDAC6/STAT3/PD-L1 pathway through the transporter UCHL1.
  4. USP10 deubiquitinates and stabilizes CD44 leading to enhanced breast cancer cell proliferation, stemness and metastasis.
  5. Transcriptomic response of overexpression ZNF32 in breast cancer cells.
  6. Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites.
  7. METTL14 suppresses the expression of YAP1 and the stemness of triple-negative breast cancer.
  1. Sci Rep. 2024 11 18. 14(1): 28475
    Down-regulation of ESRP2 inhibits breast cancer cell proliferation via inhibiting cyclinD1.
    Caiping He, Yuting Chen, Ximin Zhang, Huancun Feng, Yuzhen Rao, Tangyang Ji, Wenya Wang.
      Epithelial splicing regulatory protein 2 (ESRP2),an important alternative splicing protein of mRNA, is reported to have a dual role in tumors, which can promote or inhibit the occurrence and development of tumors. However, the function and mechanism of ESRP2 in breast cancer (BC) remain unclear. The distribution of ESRP2 expression in breast cancer and the correlation between ESRP2 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene Ontology(GO)analysis, containing biological process, cellular components, and molecular function, was utilized to evaluate the potential mechanism of ESRP2 in breast cancer. The ESRP2 expression in breast cancer cell lines was detected by real-time quantitative PCR analysis (RT-qPCR) and western blotting. Cell clone was performed to examine the proliferation of ESRP2 knockdown in MCF-7 cells. The cell cycle was measured by flow cytometry assays. The role of ESRP2 knockdown in synergistic effect with chemotherapeutic agents was also determined by MTT assay. Bioinformatics analysis demonstrated that the ESRP2 gene was elevated in breast cancer cells and its overexpression was strongly correlated with shorter overall survival. GO analysis revealed that ESRP2 expression was related to cell proliferation. ESRP2 mRNA and protein expression were elevated in breast cancer cell lines, compared to the normal human breast cell line MCF-10 A. Dwon-regulation of ESRP2 inhibited cell proliferation and promoted the sensitivity of chemotherapy drug, Cisplatin(DDP) and Paclitaxel (TAXOL), in MCF-7 cells.Additionally, ESRP2 knockdown obstructed the cell cycle at the G1 phase and caused a decrease in cyclinD1 protein expression. These findings reveal that ESRP2 is highly expressed in breast cancer and is correlated with poor prognosis in breast cancer patients. ESRP2 knockdown can inhibit MCF-7 cell proliferation by arresting the cell cycle at the G1 phase and promoting the sensitivity of chemotherapy drugs (DDP and TAXOL)in MCF-7 cells. ESRP2 may be required for the regulation of breast cancer progression, as well as a critical target for the clinical treatment of breast cancer.
    Keywords:  Breast cancer; Cell proliferation; ESRP2; Potential biomarker
    DOI:  https://doi.org/10.1038/s41598-024-77980-9
  2. Cell Mol Life Sci. 2024 Nov 23. 81(1): 461
    MicroRNA-145-5p inhibits the tumorigenesis of breast cancer through SENP2-regulated ubiquitination of ERK2.
    Xu Chen, Danqing Li, Qi Su, Xing Ling, Siyu Ding, Runxiao Xu, Zhaoxia Liu, Yuanyuan Qin, Jinping Zhang, Zhihui Yang, Xunlei Kang, Yitao Qi, Hongmei Wu.
      Breast carcinoma exhibits the highest incidence among various cancers and is the foremost cause of mortality in women. Increasing evidence shows that SUMOylation of proteins plays a critical role in the progression of breast cancer; however, the role of SENP2 and its molecular mechanism in breast cancer remain underexplored. Here, we discerned that SENP2 promoted the tumorigenesis of breast cancer both in vitro and in vivo. Furthermore, we identified that ERK2 was SUMOylated and that SENP2 played a role by deconjugating ERK2 SUMOylation in breast cancer. SUMOylation of ERK2 promoted its ubiquitin-proteasomal degradation, thus inhibiting the epithelial-to-mesenchymal transition in breast cancer cells. Furthermore, microRNA-145-5p (miR-145-5p) has emerged as a scarce commodity in breast cancer and binds to the 3'-untranslated region of SENP2 mRNA to govern the regulatory dynamics of SENP2 expression. Finally, miR-145-5p inhibits SENP2 transcription, enhances ERK2 SUMOylation, and ultimately suppresses the progression of breast cancer. These revelations suggest evolving ideas for the miR-145-5p-SENP2 axis in therapeutic intervention, thus heralding transformative prospects for the clinical management of breast cancer.
    Keywords:  Breast cancer; ERK2; MicroRNA-145-5p; SENP2; SUMOylation
    DOI:  https://doi.org/10.1007/s00018-024-05505-8
  3. Cancer Cell Int. 2024 Nov 20. 24(1): 385
    Adipose stem cell exosomes, stimulated by pro-inflammatory factors, enhance immune evasion in triple-negative breast cancer by modulating the HDAC6/STAT3/PD-L1 pathway through the transporter UCHL1.
    Qin Zhu, Kejing Zhang, Yukun Cao, Yu Hu.
       BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by high invasiveness and metastasis potential. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is strongly associated with breast cancer progression, although the underlying mechanisms are largely unknown.
    METHODS: The gene expression profiles of TNBC samples were downloaded from the TCGA database, and ubiquitination enzymes related to immune regulation were screened. UCHL1 expression in the TNBC tissues and in adipose-derived mesenchymal stem cells (ADSCs) stimulated in vitro with pro-inflammatory cytokines were analyzed. Exosomes were isolated from these stimulated ADSCs and transfected with scrambled (si-NC) or UCHL1-specific (si-UCHL1) siRNA constructs. TNBC cells were treated with the ADSCs-derived exosomes (ADSCs-Exos) and then co-cultured with macrophages or T cells. Finally, the tumorigenic potential of the ADSCs-Exos was evaluated by injecting the exosomes into mice bearing TNBC xenografts.
    RESULTS: UCHL1 was highly expressed in TNBC tissues and the stimulated ADSCs. The exosomes derived from stimulated ADSCs increased the viability and migration capacity of TNBC cells in vitro, and significantly increased Ki-67 expression through UCHL1. Furthermore, ADSCs-Exos induced M2 polarization of THP-1 monocytes by upregulating CD206 and Arg-1, and downregulating TNF-α and iNOS, and also decreased the proportion of CD3+CD8+ T cells. Mechanistically, UCHL1 regulated the STAT3 and PD-L1 signaling pathways through HDAC6. Exosomes derived from the control and cytokine-stimulated ADSCs also promoted tumor growth in vivo, and increased the expression of UCHL1, CD206, HDAC6, STAT3, and PD-L1. However, UCHL1 knockdown reversed the pro-tumorigenic effects of the ADSCs-derived exosomes in vivo and in vitro.
    CONCLUSION: Pro-inflammatory factors (IFN-γ + TNF-α) stimulating ADSCs-Exos enhance immune evasion in triple-negative breast cancer by regulating the HDAC6/STAT3/PD-L1 pathway via UCHL1 transporter. Thus, UCHL1 inhibition may enhance the response of TNBC to immunotherapy.
    Keywords:  ADSCs; Cancer progression; Immune escape; PD-L1; STAT3; Triple-negative breast cancer; UCHL1
    DOI:  https://doi.org/10.1186/s12935-024-03557-1
  4. Biochem J. 2024 Nov 20. pii: BCJ20240611. [Epub ahead of print]
    USP10 deubiquitinates and stabilizes CD44 leading to enhanced breast cancer cell proliferation, stemness and metastasis.
    Arppita Sethi, Shivkant Mishra, Vishal Upadhyay, Parul Dubey, Shumaila Siddiqui, Anil Kumar Singh, Sangita Chaowdhury, Swati Srivastava, Pragya Srivasatava, Prasannajit Sahoo, Madan Lal Brahma Bhatt, Anand Mishra, Arun Kumar Trivedi.
      Despite extensive research, strategies to effectively combat breast cancer stemness and achieve a definitive cure remains elusive. CD44, a well-defined cancer stem cell marker is reported to promote breast cancer tumorigenesis, metastasis, and chemoresistance. However, mechanisms leading to its enhanced expression and function is poorly understood. Here, we demonstrate that USP10 positively regulates CD44 protein levels and its downstream actions. While USP10 depletion prominently downregulates CD44 protein levels and functions, its overexpression significantly enhances CD44 protein levels, leading to enhanced cluster tumor cell formation, stemness, and metastasis in breast cancer cells both in vitro and ex vivo in primary human breast tumor cells. USP10 interacts with CD44 and stabilizes it through deubiquitination both in breast cancer cell lines and human breast cancer-derived primary tumor cells. Stabilized CD44 shows enhanced interaction with cytoskeleton proteins Ezrin/Radixin/Moesin and potently activates PDGFRβ/STAT3 signalling which are involved in promoting CSC traits. Using USP10 stably expressing 4T1 cells, we further demonstrate that the USP10-CD44 axis potently promotes tumorigenicity in vivo in mice, while simultaneous depletion of CD44 in these cells renders them ineffective. In line with these findings, we further showed that inhibition of USP10 either through RNAi or the pharmacological inhibitor Spautin-1 significantly mitigated CD44 levels and its downstream function ex vivo in primary breast tumor cells. Finally, we demonstrated that primary breast tumor cells are more susceptible to chemotherapy when co-treated with USP10 inhibitor indicating that the USP10-CD44 axis could be an attractive therapeutic target in combination with chemotherapy in CD44 expressing breast cancers.
    Keywords:  CD44; USP10; breast cancers; deubiquitination; metastasis
    DOI:  https://doi.org/10.1042/BCJ20240611
  5. Sci Rep. 2024 11 18. 14(1): 28407
    Transcriptomic response of overexpression ZNF32 in breast cancer cells.
    Chaosong Zhong, Dingshuang Chen, Di Gong, Xueqing Sheng, Yaqiu Lin, Ruiwen Li, Yanyan Li.
      Breast cancer is one of the deadliest malignancies in women worldwide. Zinc finger protein 32 (ZNF32) has been reported to be involved in autophagy and stem cell like properties of breast cancer cells. However, the effects, mechanisms, target genes and pathways of ZNF32 in breast cancer development have not been fully explored. In this study, stable ZNF32 overexpression breast cancer cell line was generated, and we used RNA-seq and RT-qPCR to quantify and verify the changes in transcription levels in breast cancer cells under ZNF32 overexpression. Transcriptome analysis showed that high expression of ZNF32 is accompanied by changes in downstream focal adhesion, ECM-receptor interaction, PI3K-AKT, HIPPO and TNF signaling pathways, which are critical for the occurrence and development of cancer. Multiple differentially expressed genes (DEGs) were significantly involved in cell proliferation, adhesion and migration, including 11 DEGs such as CA9, CRLF1 and ENPP2P with fundamental change of regulation modes. All the 11 DEGs were validated by RT-qPCR, and 9 of them contained potential transcriptional binding sequences of ZNF32 in their promoter region. This study provides a holistic perspective on the role and molecular mechanism of ZNF32 in breast cancer progression.
    Keywords:  Breast cancer; RNA-seq; Signaling pathway; Target genes; ZNF32
    DOI:  https://doi.org/10.1038/s41598-024-80125-7
  6. bioRxiv. 2024 Nov 02. pii: 2024.10.29.620864. [Epub ahead of print]
    Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites.
    Chin-Chih Liu, Dennis Grencewicz, Karthik Chakravarthy, Lin Li, Ruth Liepold, Matthew Wolf, Naseer Sangwan, Alice Tzeng, Rebecca Hoyd, Sachin R Jhawar, Stephen R Grobmyer, Zahraa Al-Hilli, Andrew P Sciallis, Daniel Spakowicz, Ying Ni, Charis Eng.
       Background: Breast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8+ tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8+ TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome.
    Methods: We investigated the interplay among CD8+ TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8+ TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC).
    Results: In tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8+ TILs, of which NADH, γ-glutamyltryptophan, and γ-glutamylglutamate displayed differential abundance in Staphylococcus-positive versus Staphylococcus-negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8+ TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus, the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8+ TILs.
    Conclusions: We identified specific metabolites and microbial taxa associated with CD8+ TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation.
    Keywords:  Microbiome; S. aureus; Staphylococcus; T cells; anti-tumor immunity; breast cancer; metabolism; metabolome; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1101/2024.10.29.620864
  7. J Exp Clin Cancer Res. 2024 Nov 20. 43(1): 307
    METTL14 suppresses the expression of YAP1 and the stemness of triple-negative breast cancer.
    Xupeng Bai, Jiarui Liu, Shujie Zhou, Lingzhi Wu, Xiaojie Feng, Pumin Zhang.
       BACKGROUND: Triple-negative breast cancer (TNBC) has pronounced stemness that is associated with relapse. N6-methyladenosine (m6A) plays a crucial role in shaping cellular behavior by modulating transcript expression. However, the role of m6A in TNBC stemness, as well as the mechanisms governing its abundance, has yet to be elucidated.
    METHODS: We analyzed proteomic and transcriptomic data derived from breast cancer cohorts, with an emphasis on m6A regulators. To unravel the role of m6A in TNBC, we employed RNA sequencing, methylated RNA immunoprecipitation sequencing, RNA immunoprecipitation, chromatin immunoprecipitation, and luciferase reporter assays with mesenchymal stem-like (MSL) TNBC models. The clinical relevance was validated using human tissue microarrays and publicly accessible databases.
    RESULTS: Our findings indicate that the global level of m6A modification in MSL TNBC is downregulated primarily due to the loss of methyltransferase-like 14 (METTL14). The diminished m6A modification is crucial for the maintenance of TNBC stemness, as it increases the expression of yes-associated protein 1 (YAP1) by blocking YTH domain-containing family protein 2 (YTHDF2)-mediated transcript decay, thereby promoting the activation of Hippo-independent YAP1 signaling. YAP1 is essential for sustaining the stemness regulated by METTL14. Furthermore, we demonstrated that the loss of METTL14 expression results from lysine-specific demethylase 1 (LSD1)-mediated removal of histone H3 lysine 4 methylation at the promoter region, which is critical for LSD1-driven stemness in TNBC.
    CONCLUSION: These findings present an epi-transcriptional mechanism that maintains Hippo-independent YAP1 signaling and plays a role in preserving the undifferentiated state of TNBC, which indicates the potential for targeting the LSD1-METTL14 axis to address TNBC stemness.
    Keywords:  LSD1; METTL14; Stemness; TNBC; YAP1; m6A
    DOI:  https://doi.org/10.1186/s13046-024-03225-2
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