bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒06‒09
thirteen papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.
  2. METTL3-modified lncRNA DSCAM-AS1 promotes breast cancer progression through inhibiting ferroptosis.
  3. LncRNA AFAP1-AS1 mediates breast cancer cell proliferation and migration through the miR-21/PTEN axis.
  4. Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.
  5. The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer.
  6. Exosomal lncRNA SNHG12 promotes angiogenesis and breast cancer progression.
  7. A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion.
  8. Exploring variations in glycolytic and gluconeogenic enzymes and isoforms across breast cancer cell lines and tissues.
  9. Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism.
  10. The transcriptional landscape of cancer stem-like cell functionality in breast cancer.
  11. DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.
  12. Low GPR81 in ER+ breast cancer cells drives tamoxifen resistance through inducing PPARα-mediated fatty acid oxidation.
  13. CircRNA_0044556 affects the sensitivity of triple-negative breast cancer cells to paclitaxel by regulating miR-665.
  1. Breast Cancer Res. 2024 Jun 05. 26(1): 92
    Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells.
    Xiaoxia Jin, Shuyun Yang, Xiaoyun Lu, Xudong Chen, Wencheng Dai.
      BACKGROUND: Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer.METHODS: Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells.
    RESULTS: Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident.
    CONCLUSION: ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.
    DOI:  https://doi.org/10.1186/s13058-024-01845-2
  2. J Bioenerg Biomembr. 2024 Jun 04.
    METTL3-modified lncRNA DSCAM-AS1 promotes breast cancer progression through inhibiting ferroptosis.
    Zeming Yan, Zhongzeng Liang, Kangwei Luo, Liyan Yu, Chunyan Chen, Miao Yu, Xiaojing Guo, Mingyi Li.
      Numerous studies have indicated that N6-methyladenosine (m6A) and lncRNAs play pivotal roles in human cancer. However, the underlying functions and mechanisms of m6A-lncRNA in the physiological processes of breast cancer remain unclear. Here, we found that DSCAM-AS1 is an m6A-modified lncRNA that was overexpressed in breast cancer tissues and cells, indicating poor clinical prognosis. Gain/loss functional assays suggested that DSCAM-AS1 inhibited erastin-induced ferroptosis in breast cancer cells. Mechanistically, there were remarkable m6A modification sites on both the 3'-UTR of DSCAM-AS1 and the endogenous antioxidant factor SLC7A11. M6A methyltransferase methyltransferase-like 3 (METTL3) methylated both SLC7A11 and DSCAM-AS1. Moreover, DSCAM-AS1 recognized m6A sites on the SLC7A11 mRNA, thereby enhancing its stability. Taken together, these findings indicated a potential therapeutic strategy for breast cancer ferroptosis in an m6A-dependent manner.
    Keywords:  Breast cancer; DSCAM-AS1; Ferroptosis; METTL3; N6-methyladenosine
    DOI:  https://doi.org/10.1007/s10863-024-10024-z
  3. J Cell Physiol. 2024 Jun 03.
    LncRNA AFAP1-AS1 mediates breast cancer cell proliferation and migration through the miR-21/PTEN axis.
    Dongling Quan, Huanxian Wu, Yuqin Yang, Huining Lian, Yiqing Guan, Danni Yang, Guohua Zhang, Minfeng Liu, Shaoyu Wu, Lin Lv.
      LncRNAs play various effects, mostly by sponging with miRNAs. Based on public databases integrating bioinformatics analyses and further validation in breast cancer (BC) tissue and cell lines, the effect of lncRNA AFAP1-AS1 on breast cancer cell proliferation and migration was verified. It might work via the miR-21/PTEN axis. The expression of AFAP1-AS1, which was significantly upregulated in BC tissues and cell lines, was correlated with old age and lymph node metastasis of patients with BC. Knockdown of AFAP1-AS1 inhibited the proliferation and migration of BC cells in vitro and in vivo. And downregulated miR-21 expression and upregulated PTEN expression additionally. Mechanistically, the knockdown of lncRNA AFAP1-AS1 upregulated PTEN expression and consequently attenuated miR-21-mediated enhanced BC cell proliferation and migration. LncRNA AFAP1-AS1 is a potential prognostic biomarker for BC patients.
    Keywords:  PTEN; biomarker; breast cancer; lncRNA AFAP1‐AS1; miR‐21
    DOI:  https://doi.org/10.1002/jcp.31333
  4. Mol Cancer. 2024 Jun 08. 23(1): 125
    Exosomal circSIPA1L3-mediated intercellular communication contributes to glucose metabolic reprogramming and progression of triple negative breast cancer.
    Yiran Liang, Fangzhou Ye, Dan Luo, Li Long, Yajie Wang, Yuhan Jin, Lei Wang, Yaming Li, Dianwen Han, Bing Chen, Wenjing Zhao, Lijuan Wang, Qifeng Yang.
      BACKGROUND: Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated.METHODS: RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3.
    RESULTS: Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients.
    CONCLUSIONS: Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.
    Keywords:  Breast cancer; Exosome; Glycolysis; IGF2BP3; Stemness; circSIPA1L3
    DOI:  https://doi.org/10.1186/s12943-024-02037-4
  5. Transl Oncol. 2024 Jun 05. pii: S1936-5233(24)00141-4. [Epub ahead of print]46 102014
    The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer.
    Wenqian Yu, Xiaona Lin, Shuai Leng, Yiming Hou, Zhiqiao Dang, Shishan Xue, Na Li, Fengquan Zhang.
      BACKGROUND: The transcription factor GATA4 is pivotal in cancer development but is often silenced through mechanisms like DNA methylation and histone modifications. This silencing suppresses the transcriptional activity of GATA4, disrupting its normal functions and promoting cancer progression. However, the precise molecular mechanisms and implications of GATA4 silencing in tumorigenesis remain unclear. Here, we aim to elucidate the mechanisms underlying GATA4 silencing and explore its role in breast cancer progression and its potential as a therapeutic target.METHODS: The GATA4-breast cancer prognosis link was explored via bioinformatics analyses, with GATA4 expression measured in breast tissues. Functional gain/loss experiments were performed to gauge GATA4's impact on breast cancer cell malignancy. GATA4-PRC2 complex interaction was analyzed using silver staining and mass spectrometry. Chromatin immunoprecipitation, coupled with high-throughput sequencing, was used to identify GATA4-regulated downstream target genes. The in vitro findings were validated in an in situ breast cancer xenograft mouse model.
    RESULTS: GATA4 mutation and different breast cancer subtypes were correlated, suggesting its involvement in disease progression. GATA4 suppressed cell proliferation, invasion, and migration while inducing apoptosis and senescence in breast cancer cells. The GATA4-PRC2 complex interaction silenced GATA4 expression, which altered the regulation of FAS, a GATA4 downstream gene. In vivo experiments verified that GATA4 inhibits tumor growth, suggesting its regulatory function in tumorigenesis.
    CONCLUSIONS: This comprehensive study highlights the epigenetic regulation of GATA4 and its impact on breast cancer development, highlighting the PRC2-GATA4-FAS pathway as a potential target for therapeutic interventions in breast cancers.
    Keywords:  Breast cancer; Cell senescence; Epigenetic regulation; GATA4; PRC2 complex
    DOI:  https://doi.org/10.1016/j.tranon.2024.102014
  6. Breast Cancer. 2024 Jun 04.
    Exosomal lncRNA SNHG12 promotes angiogenesis and breast cancer progression.
    Yan Chen, Yuxin Zhou, Jiafeng Chen, Jiahui Yang, Yijie Yuan, Weizhu Wu.
      OBJECTIVE: Breast cancer is one of the most prevalent malignancies in women. Exosomes are important mediators of intercellular communication; however, their regulatory mechanisms in human umbilical vein endothelial cells (HUVECs) angiogenesis in breast cancer remain unknown.METHODS: We isolated and characterized breast cancer cell-derived exosomes and investigated their functions. Exosomal sequencing and the TCGA database were used to screen long non-coding RNA (lncRNA). In vitro and in vivo experiments were performed to investigate the role of exosomal lncRNA in HUVEC angiogenesis and tumor growth. Molecular methods were used to demonstrate the molecular mechanism of lncRNA.
    RESULTS: We demonstrated that breast cancer cell-derived exosomes promoted HUVEC proliferation, tube formation, and migration. Combining exosomal sequencing results with The Cancer Genome Atlas Breast Cancer database, we screened lncRNA small nucleolar RNA host gene 12 (SNHG12), which was highly expressed in breast cancer cells. SNHG12 was also upregulated in HUVECs co-cultured with exosome-overexpressed SNHG12. Moreover, overexpression of SNHG12 in exosomes increased HUVEC proliferation and migration, whereas deletion of SNHG12 in exosomes showed the opposite effects. In vivo experiments showed that SNHG12 knockdown in exosomes inhibited breast cancer tumor growth. Transcriptome sequencing identified MMP10 as the target gene of SNHG12. Functional experiments revealed that MMP10 overexpression promoted HUVEC angiogenesis. Mechanistically, SNHG12 blocked the interaction between PBRM1 and MMP10 by directly binding to PBRM1. Moreover, exosomal SNHG12 promoted HUVEC angiogenesis via PBRM1 and MMP10.
    CONCLUSIONS: In summary, our findings confirmed that exosomal SNHG12 promoted HUVEC angiogenesis via the PBRM1-MMP10 axis, leading to enhanced malignancy of breast cancer. Exosomal SNHG12 may be a novel therapeutic target for breast cancer.
    Keywords:  Angiogenesis; Breast cancer; Exosomes; Progression; lncRNA SNHG12
    DOI:  https://doi.org/10.1007/s12282-024-01574-6
  7. Nat Commun. 2024 Jun 07. 15(1): 4866
    A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion.
    Antoine A Khalil, Daan Smits, Peter D Haughton, Thijs Koorman, Karin A Jansen, Mathijs P Verhagen, Mirjam van der Net, Kitty van Zwieten, Lotte Enserink, Lisa Jansen, Abdelrahman G El-Gammal, Daan Visser, Milena Pasolli, Max Tak, Denise Westland, Paul J van Diest, Cathy B Moelans, M Guy Roukens, Sandra Tavares, Anne-Marie Fortier, Morag Park, Riccardo Fodde, Martijn Gloerich, Fried J T Zwartkruis, Patrick Wb Derksen, Johan de Rooij.
      Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.
    DOI:  https://doi.org/10.1038/s41467-024-49230-z
  8. Carbohydr Res. 2024 May 31. pii: S0008-6215(24)00148-4. [Epub ahead of print]541 109169
    Exploring variations in glycolytic and gluconeogenic enzymes and isoforms across breast cancer cell lines and tissues.
    Carla Luís, Rúben Fernandes, Raquel Soares.
      It is well established that tumour cells undergo metabolic changes to acquire biological advantage over normal cells with activation of the glycolytic pathway, a process termed "Warburg effect". Enzyme isoforms are alternative enzymatic forms with the same function but with different biochemical or epigenetic features. Moreover, isoforms may have varying impacts on different metabolic pathways. We challenge ourselves to analyse the glycolytic and gluconeogenic enzymes and isoforms in breast cancer, a complex and heterogeneous pathology, associated with high incidence and mortality rates especially among women. We analysed epithelial and tumour cell lines by RT-PCR and compared values to a publicly available database for the expression profile of normal and tumour tissues (Gepia) of enzymes and enzymatic isoforms from glycolytic and gluconeogenic pathways. Additionally, GeneMANIA was used to evaluate interactions, pathways, and attributes of each glycolytic/gluconeogenic steps. The findings reveal that the enzymes and enzymatic isoforms expressed in cell culture were somewhat different from those in breast tissue. We propose that the tumor microenvironment plays a crucial role in the expression of glycolytic and gluconeogenic enzymes and isoforms in tumour cells. Nonetheless, they not only participate in glycolytic and gluconeogenic enzymatic activities but may also influence other pathways, such as the Pentose-Phosphate-Pathway, TCA cycle, as well as other carbohydrate, lipid, and amino acid metabolism.
    Keywords:  Breast cancer; Enzymes; Gluconeogenesis; Glycolysis; Isoforms; Metabolism
    DOI:  https://doi.org/10.1016/j.carres.2024.109169
  9. Cancer Cell Int. 2024 Jun 05. 24(1): 199
    Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism.
    Madison R Pickett, Yuan-I Chen, Mohini Kamra, Sachin Kumar, Nikhith Kalkunte, Gabriella P Sugerman, Kelsey Varodom, Manuel K Rausch, Janet Zoldan, Hsin-Chin Yeh, Sapun H Parekh.
      The extracellular matrix (ECM) is a dynamic and complex microenvironment that modulates cell behavior and cell fate. Changes in ECM composition and architecture have been correlated with development, differentiation, and disease progression in various pathologies, including breast cancer [1]. Studies have shown that aligned fibers drive a pro-metastatic microenvironment, promoting the transformation of mammary epithelial cells into invasive ductal carcinoma via the epithelial-to-mesenchymal transition (EMT) [2]. The impact of ECM orientation on breast cancer metabolism, however, is largely unknown. Here, we employ two non-invasive imaging techniques, fluorescence-lifetime imaging microscopy (FLIM) and intensity-based multiphoton microscopy, to assess the metabolic states of cancer cells cultured on ECM-mimicking nanofibers in a random and aligned orientation. By tracking the changes in the intrinsic fluorescence of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, as well as expression levels of metastatic markers, we reveal how ECM fiber orientation alters cancer metabolism and EMT progression. Our study indicates that aligned cellular microenvironments play a key role in promoting metastatic phenotypes of breast cancer as evidenced by a more glycolytic metabolic signature on nanofiber scaffolds of aligned orientation compared to scaffolds of random orientation. This finding is particularly relevant for subsets of breast cancer marked by high levels of collagen remodeling (e.g. pregnancy associated breast cancer), and may serve as a platform for predicting clinical outcomes within these subsets [3-6].
    Keywords:  Breast cancer microenvironment; Cellular metabolism; Epithelial-to-mesenchymal transition (EMT); Extracellular matrix (ECM); Fluorescence lifetime imaging microscopy (FLIM); Optical redox ratio (ORR)
    DOI:  https://doi.org/10.1186/s12935-024-03385-3
  10. J Transl Med. 2024 Jun 03. 22(1): 530
    The transcriptional landscape of cancer stem-like cell functionality in breast cancer.
    Oana Baldasici, Olga Soritau, Andrei Roman, Carmen Lisencu, Simona Visan, Laura Maja, Bogdan Pop, Bogdan Fetica, Andrei Cismaru, Laurian Vlase, Loredana Balacescu, Ovidiu Balacescu, Aman Russom, Oana Tudoran.
      BACKGROUND: Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However, due to lack of specific molecular markers, increased phenotypic plasticity and no clear clinicopathological features, the assessment of CSCs presence and functionality in solid tumors is challenging. While several potential markers, such as CD24/CD44, have been proposed, the extent to which they truly represent the stem cell potential of tumors or merely provide static snapshots is still a subject of controversy. Recent studies have highlighted the crucial role of the tumor microenvironment (TME) in influencing the CSC phenotype in breast cancer. The interplay between the tumor and TME induces significant changes in the cancer cell phenotype, leading to the acquisition of CSC characteristics, therapeutic resistance, and metastatic spread. Simultaneously, CSCs actively shape their microenvironment by evading immune surveillance and attracting stromal cells that support tumor progression.METHODS: In this study, we associated in vitro mammosphere formation assays with bulk tumor microarray profiling and deconvolution algorithms to map CSC functionality and the microenvironmental landscape in a large cohort of 125 breast tumors.
    RESULTS: We found that the TME score was a significant factor associated with CSC functionality. CSC-rich tumors were characterized by an immune-suppressed TME, while tumors devoid of CSC potential exhibited high immune infiltration and activation of pathways involved in the immune response. Gene expression analysis revealed IFNG, CXCR5, CD40LG, TBX21 and IL2RG to be associated with the CSC phenotype and also displayed prognostic value for patients with breast cancer.
    CONCLUSION: These results suggest that the characterization of CSCs content and functionality in tumors can be used as an attractive strategy to fine-tune treatments and guide clinical decisions to improve patients therapy response.
    DOI:  https://doi.org/10.1186/s12967-024-05281-w
  11. Transl Oncol. 2024 Jun 05. pii: S1936-5233(24)00143-8. [Epub ahead of print]46 102016
    DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.
    Xuliren Wang, Weiru Chi, Yuwei Ma, Qi Zhang, Jingyan Xue, Zhi-Ming Shao, Bingqiu Xiu, Jiong Wu, Yayun Chi.
      BACKGROUND: Breast cancer (BC) poses a global threat, with HER2-positive BC being a particularly hazardous subtype. Despite the promise shown by neoadjuvant therapy (NAT) in improving prognosis, resistance in HER2-positive BC persists despite emerging targeted therapies. The objective of this study is to identify markers that promote therapeutic sensitivity and unravel the underlying mechanisms.METHODS: We conducted an analysis of 86 HER2-positive BC biopsy samples pre-NAT using RNA-seq. Validation was carried out using TCGA, Kaplan‒Meier Plotter, and Oncomine databases. Phenotype verification utilized IC50 assays, and prognostic validation involved IHC on tissue microarrays. RNA-seq was performed on wild-type/DUSP4-KO cells, while RT‒qPCR assessed ROS pathway regulation. Mechanistic insights were obtained through IP and MS assays.
    RESULTS: Our findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER2-positive BC. Moreover, DUSP4 hinders G6PD activity via ALDOB dephosphorylation, with a noteworthy association with heightened ROS levels.
    CONCLUSIONS: In summary, our study unveils a metabolic reprogramming paradigm in BC, highlighting DUSP4's role in enhancing therapeutic sensitivity in HER2-positive BC cells. DUSP4 interacts with ALDOB, inhibiting G6PD activity and the ROS pathway, establishing it as an independent prognostic predictor for HER2-positive BC patients.
    Keywords:  ALDOB; Breast cancer; DUSP4; Drug sensitivity; G6PD; HER2; ROS
    DOI:  https://doi.org/10.1016/j.tranon.2024.102016
  12. Life Sci. 2024 May 31. pii: S0024-3205(24)00353-9. [Epub ahead of print]350 122763
    Low GPR81 in ER+ breast cancer cells drives tamoxifen resistance through inducing PPARα-mediated fatty acid oxidation.
    Jing Yu, Yongjun Du, Chang Liu, Yu Xie, Mengci Yuan, Meihua Shan, Ning Li, Chang Liu, Yue Wang, Junfang Qin.
      AIMS: The intricate molecular mechanisms underlying estrogen receptor-positive (ER+) breast carcinogenesis and resistance to endocrine therapy remain elusive. In this study, we elucidate the pivotal role of GPR81, a G protein-coupled receptor, in ER+ breast cancer (BC) by demonstrating low expression of GPR81 in tamoxifen (TAM)-resistant ER+ BC cell lines and tumor samples, along with the underlying molecular mechanisms.MAIN METHODS: Fatty acid oxidation (FAO) levels and lipid accumulation were explored using MDA and FAβO assay, BODIPY 493/503 staining, and Lipid TOX staining. Autophagy levels were assayed using CYTO-ID detection and Western blotting. The impact of GPR81 on TAM resistance in BC was investigated through CCK8 assay, colony formation assay and a xenograft mice model.
    RESULTS: Aberrantly low GPR81 expression in TAM-resistant BC cells disrupts the Rap1 pathway, leading to the upregulation of PPARα and CPT1. This elevation in PPARα/CPT1 enhances FAO, impedes lipid accumulation and lipid droplet (LD) formation, and subsequently inhibits cell autophagy, ultimately promoting TAM-resistant BC cell growth. Moreover, targeting GPR81 and FAO emerges as a promising therapeutic strategy, as the GPR81 agonist and the CPT1 inhibitor etomoxir effectively inhibit ER+ BC cell and tumor growth in vivo, re-sensitizing TAM-resistant ER+ cells to TAM treatment.
    CONCLUSION: Our data highlight the critical and functionally significant role of GPR81 in promoting ER+ breast tumorigenesis and resistance to endocrine therapy. GPR81 and FAO levels show potential as diagnostic biomarkers and therapeutic targets in clinical settings for TAM-resistant ER+ BC.
    Keywords:  Autophagy; Fatty acid oxidation; GPR81; PPARα; Tamoxifen resistance
    DOI:  https://doi.org/10.1016/j.lfs.2024.122763
  13. J Chemother. 2024 Jun 07. 1-9
    CircRNA_0044556 affects the sensitivity of triple-negative breast cancer cells to paclitaxel by regulating miR-665.
    Jing-Jing Chen, Peng Shi, Zhi-Chao Cui, Nan Jiang, Jie Ma.
      CircRNAs have been implicated in the development of resistance in triple-negative breast cancer (TNBC). However, the association between circRNA_0044556 and paclitaxel (PTX) resistance in TNBC is still limited. Therefore, the purpose of this study was to investigate the effect of circRNA_0044556 on biological function and PTX resistance in TNBC cells. PTX-resistant TNBC cells (MDA-MB-231/PTX) were obtained by continuously exposing MDA-MB-231 cells to increasing paclitaxel levels. The expression levels of circRNA_0044556 and miR-665 were measured by qRT-PCR. The regulatory relationship between miR-665 and circRNA_0044556 was verified by biological information website analysis and double-luciferase reporter gene detection experiments. MTT assay, clone assay, flow cytometry and Western blot analysis were used to evaluate the influence of cell biological function. Elevated circRNA_0044556 was observed in TNBC, and paclitaxel increased the expression of circRNA_0044556 in TNBC cells. In TNBC, circRNA_0044556 acted as a ceRNA for miR-665. In addition, low expression of circRNA_0044556 combined with miR-665 inhibited the proliferation of TNBC cells and paclitaxel-resistant TNBC cells while inducing cell death. Our study demonstrated that the downregulation of circRNA_0044556 inhibits the malignant progression of TNBC cells and paclitaxel resistance via miR-665. Thus, circRNA_0044556 may be a potential therapeutic target for PTX-resistance TNBC.
    Keywords:  Triple-negative breast cancer; circRNA_0044556; miR-665; paclitaxel resistance
    DOI:  https://doi.org/10.1080/1120009X.2024.2345028
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