bims-merabr 2024-06-02 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2024‒06‒02
twelve papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

KLF11 promotes the proliferation of breast cancer cells by inhibiting p53-MDM2 signaling.
Bestatin attenuates breast cancer stemness by targeting puromycin-sensitive aminopeptidase.
Her2 amplification, Rel-A, and Bach1 can influence APOBEC3A expression in breast cancer cells.
Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.
The role of IL-1B in breast cancer bone metastasis.
EDI3 knockdown in ER-HER2+ breast cancer cells reduces tumor burden and improves survival in two mouse models of experimental metastasis.
Circ_RPPH1 facilitates progression of breast cancer via miR-1296-5p/TRIM14 axis.
TROP2 promotes the proliferation of triple-negative breast cancer cells via calcium ion-dependent ER stress signaling pathway.
Identification of Potential Breast Cancer Stem Cell Biomarkers in the Secretome Using a Network Interaction Approach Analysis.
A Potential Combination of Targeting HSP90 and mTOR in Breast Cancer Cell Growth, Migration, and Invasion Through Inhibiting AKT Phosphorylation and F-actin Organization.
Loss of RBM45 inhibits breast cancer progression by reducing the SUMOylation of IRF7 to promote IFNB1 transcription.
Overexpression of COL11A1 confers tamoxifen resistance in breast cancer.

Cell Signal. 2024 May 27. pii: S0898-6568(24)00206-7. [Epub ahead of print]120 111238

KLF11 promotes the proliferation of breast cancer cells by inhibiting p53-MDM2 signaling.

Zhi-Han Hou, Min Tao, Jiang Dong, Hong-Mei Qiu, Fan Li, Xiao-Yan Bai.

  Abnormal Krüppel-like factor 11 (KLF11) expression is frequently found in tumor tissues and is associated with cancer prognosis, but its biological functions and corresponding mechanisms remain elusive. Here, we demonstrated that KLF11 functions as an oncoprotein to promote tumor proliferation in breast cancer cells. Mechanistically, at the transcription level, KLF11 decreased TP53 mRNA expression. Notably, KLF11 also interacted with and stabilized MDM2 through inhibiting MDM2 ubiquitination and subsequent degradation. This increase in MDM2 in turn accelerated the ubiquitin-mediated proteolysis of p53, leading to the reduced expression of p53 and its target genes, including CDKN1A, BAX, and NOXA1. Accordingly, data from animals further confirmed that KLF11 significantly upregulated the growth of breast cancer cells and was inversely correlated with p53 expression. Taken together, our findings reveal a novel mechanism for breast cancer progression in which the function of the tumor suppressor p53 is dramatically weakened.

Keywords:  Breast cancer; Krüppel-like factor 11; MDM2; Proliferation; p53

DOI:  https://doi.org/10.1016/j.cellsig.2024.111238
Discov Oncol. 2024 May 30. 15(1): 197

Bestatin attenuates breast cancer stemness by targeting puromycin-sensitive aminopeptidase.

Yan Ma, Xintong Yang, Pengge Pan, Jinyi Yang, Xiaojuan Wu, Danhan Wang, Hui Gao.

  Breast cancer is a prevalent malignant tumor among women with an increasing incidence rate annually. Breast cancer stem cells (BCSCs) are integral in impeding tumor advancement and addressing drug resistance. Bestatin serves as an adjuvant chemotherapy, triggering apoptosis in cancer cells. In this study, the effects of bestatin on sorted BCSCs from breast cancer cell lines have been studied. Our results indicated that bestatin inhibits the migration and proliferation of breast cancer cells by reducing the stemness of BCSCs both in vitro and in vivo. Puromycin-sensitive aminopeptidase is implicated in the process through the regulation of cell cycle, resulting in heightened cell apoptosis and diminished cell proliferation of BCSCs. Our study suggest that targeting cancer stem cell may offer a promising approach in breast cancer treatment, presenting noval therapeutic strategies for patients with breast cancer.

Keywords:  Apoptosis; Bestatin; Breast cancer; Breast cancer stem cells; Proliferation; Puromycin-sensitive aminopeptidase

DOI:  https://doi.org/10.1007/s12672-024-01063-4
PLoS Genet. 2024 May 28. 20(5): e1011293

Her2 amplification, Rel-A, and Bach1 can influence APOBEC3A expression in breast cancer cells.

Madeline Dennis, Alyssa Hurley, Nicholas Bray, Cameron Cordero, Jose Ilagan, Tony M Mertz, Steven A Roberts.

APOBEC-induced mutations occur in 50% of sequenced human tumors, with APOBEC3A (A3A) being a major contributor to mutagenesis in breast cancer cells. The mechanisms that cause A3A activation and mutagenesis in breast cancers are still unknown. Here, we describe factors that influence basal A3A mRNA transcript levels in breast cancer cells. We found that basal A3A mRNA correlates with A3A protein levels and predicts the amount of APOBEC signature mutations in a panel of breast cancer cell lines, indicating that increased basal transcription may be one mechanism leading to breast cancer mutagenesis. We also show that alteration of ERBB2 expression can drive A3A mRNA levels, suggesting the enrichment of the APOBEC mutation signature in Her2-enriched breast cancer could in part result from elevated A3A transcription. Hierarchical clustering of transcripts in primary breast cancers determined that A3A mRNA was co-expressed with other genes functioning in viral restriction and interferon responses. However, reduction of STAT signaling via inhibitors or shRNA in breast cancer cell lines had only minor impact on A3A abundance. Analysis of single cell RNA-seq from primary tumors indicated that A3A mRNA was highest in infiltrating immune cells within the tumor, indicating that correlations of A3A with STAT signaling in primary tumors may be result from higher immune infiltrates and are not reflective of STAT signaling controlling A3A expression in breast cancer cells. Analysis of ATAC-seq data in multiple breast cancer cell lines identified two transcription factor sites in the APOBEC3A promoter region that could promote A3A transcription. We determined that Rel-A, and Bach1, which have binding sites in these peaks, elevated basal A3A expression. Our findings highlight a complex and variable set of transcriptional activators for A3A in breast cancer cells.

DOI: https://doi.org/10.1371/journal.pgen.1011293
Nat Commun. 2024 May 29. 15(1): 4549

Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Xianhui Ruan, Wei Yan, Minghui Cao, Ray Anthony M Daza, Miranda Y Fong, Kaifu Yang, Jun Wu, Xuxiang Liu, Melanie Palomares, Xiwei Wu, Arthur Li, Yuan Chen, Rahul Jandial, Nicholas C Spitzer, Robert F Hevner, Shizhen Emily Wang.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

DOI: https://doi.org/10.1038/s41467-024-48740-0
J Bone Oncol. 2024 Jun;46 100608

The role of IL-1B in breast cancer bone metastasis.

Jiabao Zhou, Penelope D Ottewell.

  Interleukin-1B (IL-1B) is a potent pro-inflammatory cytokine that plays multiple, pivotal roles, in the complex interplay between breast cancer cells and the bone microenvironment. IL-1B is involved in the growth of the primary tumours, regulation of inflammation within the tumour microenvironment, promotion of epithelial to mesenchymal transition (EMT), migration and invasion. Moreover, when breast cancer cells arrive in the bone microenvironment there is an upregulation of IL-1B which promotes the creation of a conducive niche for metastatic breast cancer cells as well as stimulating initiation of the vicious cycle of bone metastasis. Pre-clinical studies have demonstrated that inhibition of IL-1 signalling reduces bone metastasis from oestrogen receptor positive/triple-negative breast cancers in various mouse models. However, effects on primary tumours and soft tissue metastasis remain controversial with some studies showing increased tumour growth in these sites, whilst others show no effects. Notably, combining anti-IL-1 therapy with standard-of-care treatments, such as chemotherapy and immunotherapy, has been demonstrated to reduce the growth of primary tumours, bone metastasis, as well as metastatic outgrowth in other organs. This review focuses on the mechanisms by which IL-1B promotes breast cancer bone metastasis.

Keywords:  Bone metastasis; Breast cancer; Interleukin-1B

DOI:  https://doi.org/10.1016/j.jbo.2024.100608
Breast Cancer Res. 2024 May 30. 26(1): 87

EDI3 knockdown in ER-HER2+ breast cancer cells reduces tumor burden and improves survival in two mouse models of experimental metastasis.

Annika Glotzbach, Katharina Rohlf, Anastasia Gonscharow, Simon Lüke, Özlem Demirci, Brigitte Begher-Tibbe, Nina Overbeck, Jörg Reinders, Cristina Cadenas, Jan G Hengstler, Karolina Edlund, Rosemarie Marchan.

  BACKGROUND: Despite progress understanding the mechanisms underlying tumor spread, metastasis remains a clinical challenge. We identified the choline-producing glycerophosphodiesterase, EDI3 and reported its association with metastasis-free survival in endometrial cancer. We also observed that silencing EDI3 slowed cell migration and other cancer-relevant phenotypes in vitro. Recent work demonstrated high EDI3 expression in ER-HER2+ breast cancer compared to the other molecular subtypes. Silencing EDI3 in ER-HER2+ cells significantly reduced cell survival in vitro and decreased tumor growth in vivo. However, a role for EDI3 in tumor metastasis in this breast cancer subtype was not explored. Therefore, in the present work we investigate whether silencing EDI3 in ER-HER2+ breast cancer cell lines alters phenotypes linked to metastasis in vitro, and metastasis formation in vivo using mouse models of experimental metastasis.METHODS: To inducibly silence EDI3, luciferase-expressing HCC1954 cells were transduced with lentiviral particles containing shRNA oligos targeting EDI3 under the control of doxycycline. The effect on cell migration, adhesion, colony formation and anoikis was determined in vitro, and significant findings were confirmed in a second ER-HER2+ cell line, SUM190PT. Doxycycline-induced HCC1954-luc shEDI3 cells were injected into the tail vein or peritoneum of immunodeficient mice to generate lung and peritoneal metastases, respectively and monitored using non-invasive bioluminescence imaging. Metabolite levels in cells and tumor tissue were analyzed using targeted mass spectrometry and MALDI mass spectrometry imaging (MALDI-MSI), respectively.
RESULTS: Inducibly silencing EDI3 reduced cell adhesion and colony formation, as well as increased susceptibility to anoikis in HCC1954-luc cells, which was confirmed in SUM190PT cells. No influence on cell migration was observed. Reduced luminescence was seen in lungs and peritoneum of mice injected with cells expressing less EDI3 after tail vein and intraperitoneal injection, respectively, indicative of reduced metastasis. Importantly, mice injected with EDI3-silenced cells survived longer. Closer analysis of the peritoneal organs revealed that silencing EDI3 had no effect on metastatic organotropism but instead reduced metastatic burden. Finally, metabolic analyses revealed significant changes in choline and glycerophospholipid metabolites in cells and in pancreatic metastases in vivo.
CONCLUSIONS: Reduced metastasis upon silencing supports EDI3's potential as a treatment target in metastasizing ER-HER2+ breast cancer.

Keywords:  Anoikis; Breast cancer; Choline metabolism; GPCPD1; Glycerophospholipid metabolism; HER2 positive breast cancer; Metastasis

DOI:  https://doi.org/10.1186/s13058-024-01849-y
Cancer Biol Ther. 2024 Dec 31. 25(1): 2360768

Circ_RPPH1 facilitates progression of breast cancer via miR-1296-5p/TRIM14 axis.

Jing Jiang, Shenghong Shi, Wei Zhang, Chao Li, Long Sun, Qidong Ge, Xujun Li.

  Circular RNA Ribonuclease PRNA Component H1 (circ_RPPH1) and microRNA (miRNA) miR-1296-5p play a crucial role in breast cancer (BC), but the molecular mechanism is vague. Evidence showed that miR-1296-5p can activate tripartite motif-containing 14 (TRIM14). Clinical indications of eighty BC patients were collected and the circ_RPPH1 expression was detected using real-time quantitative PCR. MCF-7 and MDA-MB-231 cells were transfected with overexpression or knockdown of circ_RPPH1, miR-1296-5p, or TRIM14. Cell counting kit-8, cell cloning formation, wound healing, Transwell, and flow cytometry assays were performed to investigate the malignant phenotype of BC. The dual-luciferase reporter gene analyses were applied to reveal the interaction between these target genes. Subcutaneous tumorigenic model mice were established with circ_RPPH1 overexpression MDA-MB-231 cells in vivo; the tumor weight and volume, levels of miR-1296-5 and TRIM14 mRNA were measured. Western blot and immunohistochemistry were used to detect TRIM14 in cells and mice. Circ_RPPH1 levels were notably higher in BC patients and have been found to promote cell proliferation, invasion, and migration of BC cells. Circ_RPPH1 altered cell cycle and hindered apoptosis. Circ_RPPH1 knockdown or miR-1296-5p overexpression inhibited the malignant phenotype of BC. Furthermore, miR-1296-5p knockdown reversed circ_RPPH1's promotion effects on BC. Interestingly, TRIM14 overexpression counteracts the inhibitory effects of miR-1296-5p overexpression and circ_RPPH1 silencing on BC. Moreover, in BC tumor-bearing mice, circ_RPPH1 overexpression led to increased TRIM14 expression and facilitated tumor growth. Circ_RPPH1 enhanced BC progression through miR-1296-5p/TRIM14 axis, indicating its potential as a biomarker and therapeutic target in BC.

Keywords:  Breast cancer; circular RNA ribonuclease P RNA component H1; microRNA-1296-5p; tripartite motif-containing 14

DOI:  https://doi.org/10.1080/15384047.2024.2360768
Cell Biochem Biophys. 2024 May 30.

TROP2 promotes the proliferation of triple-negative breast cancer cells via calcium ion-dependent ER stress signaling pathway.

Ning Li, Jianzhong Xu, Xi Yan, Qing Liu, Mingqi Zhang.

  OBJECTIVE: To explore the molecular mechanisms of tumor-associated calcium signal transduction factor 2 (TROP2) affecting the occurrence and development of triple-negative breast cancer (TNBC).METHODS: The TCGA database, immunohistochemical staining, and qRT-PCR were used to analyze the expression of TROP2 in TNBC tissues and cells. The protein expressions of TROP2 and inositol 1,4,5-trisphosphate receptor (IP3R) after TROP2 knockdown were detected by western blot (WB). Cell proliferation was detected by CCK8 and colony formation assay, Annexin V-APC/PI flow cytometry was used to detect apoptosis, and intracellular calcium ion (Ca2+) was detected by flow cytometry with Fura 2-AM fluorescent probe. Finally, the morphological changes of the endoplasmic reticulum (ER) were observed by transmission electron microscopy, and the expression of ER stress (ERS)-related proteins was detected by WB and immunofluorescence staining.
RESULTS: TROP2 was up-regulated in TNBC tumor tissues and cells. Silencing TROP2 decreased the proliferation rate and clone formation number, and increased the apoptosis rate and the Ca2+ level in TNBC cells. These phenomena were reversed after the addition of 2-APB. In addition, after TROP2 knockdown, the expressions of IP3R and ERS-related proteins were up-regulated, the ER was cystic dilated, and ERS was activated. And the addition of 2-APB significantly inhibited the activation of ERS induced by TROP2 knockdown.
CONCLUSION: TROP2 regulated the proliferation and apoptosis of TNBC cells through a Ca2+-dependent ERS signaling pathway.

Keywords:  Calcium release channel; Endoplasmic reticulum stress; Triple-negative breast cancer; Tumor-associated calcium signal transducer 2

DOI:  https://doi.org/10.1007/s12013-024-01327-4
Asian Pac J Cancer Prev. 2024 May 01. pii: 91164. [Epub ahead of print]25(5): 1803-1813

Identification of Potential Breast Cancer Stem Cell Biomarkers in the Secretome Using a Network Interaction Approach Analysis.

Ay Ly Margaret, Septelias Inawati Wanandi, Fadilah Fadilah, Rafika Indah Paramita.

  BACKGROUND: Breast cancer stem cells (BCSCs) play a role in the high rates of resistance, recurrence, and metastasis. The precise biomarkers of BCSCs can assist effectively in identifying cancer, assessing prognosis, diagnosing, and monitoring therapy. The aim of this study was to give a complete analysis for predicting specific biomarkers of BCSCs.METHODS: We aggregated profile datasets in this work to shed light on the underlying critical genes and pathways of BCSCs. We obtained two expression profiling by array datasets (GSE7513 and GSE7515) from the Gene Expression Omnibus (GEO) database to identify biomarkers in BCSCs. Enrichr was used to do functional analysis, including gene ontology (GO) and reactome pathway. Furthermore, the protein-protein interaction (PPI) of these differential expression genes (DEGs) was visualized using Cytoscape with the search tool for the retrieval of interacting genes (STRING). The hub genes in the PPI network were chosen for further investigation.
RESULTS: We identified 65 up-regulated and 190 down- regulated DEGs and the GO enrichment analysis revealed that these DEGs were enriched in biological process related to tumorigenesis and stemness, including alter the extracellular matrix's physicochemical properties, cytoskeletal reorganisation, adhesion, motility, migration, growth, and survival. The Reactome analysis indicated that these DEGs were also involved in modulating function of ECM, regulation cancer metabolism and angiogenesis, tumor growth, proliferation, and metastasis.
CONCLUSION: Our bioinformatic study revealed that FYN, INADL, OCLN, F11R, and TOP2A were potential biomarker panel of BCSCs from secretome.

Keywords:  Bioinformatics; Biomarker; Secretome; breast cancer stem cells; network interaction

DOI:  https://doi.org/10.31557/APJCP.2024.25.5.1803
Anticancer Res. 2024 Jun;44(6): 2555-2565

A Potential Combination of Targeting HSP90 and mTOR in Breast Cancer Cell Growth, Migration, and Invasion Through Inhibiting AKT Phosphorylation and F-actin Organization.

Prasit Suwannalert, Pimchanok Panpinyaporn, Pitchapa Wantanachaisaeng, Teerapat Teeppaibul, Wilunplus Khumsri, Thidarat Koomsang, Witchuda Payuhakrit, Chonnapat Naktubtim.

  BACKGROUND/AIM: Breast cancer is the most prevalent form of cancer among women worldwide, with a high mortality rate. While the most common cause of breast cancer death is metastasis, there is currently no potential treatment for patients at the metastatic stage. The present study investigated the potential of using a combination of HSP90 and mTOR inhibitor in the treatment of breast cancer cell growth, migration, and invasion.MATERIALS AND METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) was used to investigate the gene expression profiles. Western blot analysis and fluorescence staining were used for protein expression and localization, respectively. MTT, wound healing, and transwell invasion assays were used for cell proliferation, migration, and invasion, respectively.
RESULTS: GEPIA demonstrated that HSP90 expression was significantly higher in breast invasive carcinoma compared to other tumor types, and this expression correlated with mTOR levels. Treatment with 17-AAG, an HSP90 inhibitor, and Torkinib, an mTORC1/2 inhibitor, significantly inhibited cell proliferation. Moreover, combination treatment led to down-regulation of AKT. Morphological changes revealed a reduction in F-actin intensity, a marked reduction of YAP, with interference in nuclear localization.
CONCLUSION: Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment.

Keywords:  AKT; Breast cancer; F-actin; HSP90; invasion; mTOR; migration

DOI:  https://doi.org/10.21873/anticanres.17061
Cancer Lett. 2024 May 24. pii: S0304-3835(24)00382-3. [Epub ahead of print] 216988

Loss of RBM45 inhibits breast cancer progression by reducing the SUMOylation of IRF7 to promote IFNB1 transcription.

Yuesheng Lv, Siwen Sun, Jinrui Zhang, Chong Wang, Chaoqun Chen, Qianyi Zhang, Jinyao Zhao, Yangfan Qi, Wenjing Zhang, Yang Wang, Man Li.

  Type I interferons exhibit anti-proliferative and anti-cancer activities, but their detailed regulatory mechanisms in cancer have not been fully elucidated yet. RNA binding proteins are master orchestrators of gene regulation, which are closely related to tumor progression. Here we show that the upregulated RNA binding protein RBM45 correlates with poor prognosis in breast cancer. Depletion of RBM45 suppresses breast cancer progression both in cultured cells and xenograft mouse models. Mechanistically, RBM45 ablation inhibits breast cancer progression through regulating type I interferon signaling, particularly by elevating IFN-β production. Importantly, RBM45 recruits TRIM28 to IRF7 and stimulates its SUMOylation, thereby repressing IFNB1 transcription. Loss of RBM45 reduced the SUMOylation of IRF7 by reducing the interaction between TRIM28 and IRF7 to promote IFNB1 transcription, leading to the inhibition of breast cancer progression. Taken together, our finding uncovers a vital role of RBM45 in modulating type I interferon signaling and cancer aggressive progression, implicating RBM45 as a potential therapeutic target in breast cancer.

Keywords:  IFNB1; IRF7; RBM45; SUMOylation; breast cancer

DOI:  https://doi.org/10.1016/j.canlet.2024.216988
NPJ Breast Cancer. 2024 May 28. 10(1): 38

Overexpression of COL11A1 confers tamoxifen resistance in breast cancer.

Chengxiao Fu, Shan Duan, Xiaoming Zhou, Yingcai Meng, Xisha Chen.

Breast cancer is the most commonly diagnosed malignancy and benefits from endocrine agents such as tamoxifen. However, the development of drug resistance in cancerous cells often leads to recurrence, thus limiting the therapeutic benefit. Identification of potential biomarkers that can predict response to tamoxifen and recognize patients who will clinically benefit from this therapy is urgently needed. In this study, we report that high collagen type XI alpha 1 (COL11A1) expression was associated with poor therapeutic response and prognosis in breast cancer patients treated with tamoxifen. To confirm the role of COL11A1 in the development of tamoxifen resistance, we established MCF-7/COL11A1 and T47D/COL11A1 cell lines, which stably expressed COL11A1. Compared with parental MCF-7 and T47D, MCF-7/COL11A1 and T47D/COL11A1 cells were more resistant to 4-OHT-induced growth inhibition. Moreover, the level of COL11A1 expression was upregulated in tamoxifen-resistant MCF-7/TamR and T47D/TamR cell lines, and depletion of COL11A1 markedly sensitized the cells to 4-OHT in vitro and in vivo. Interestingly, the level of estrogen receptor α (ERα) expression was elevated, probably due to the increased COL11A1 in TamR cells. In addition, knockdown of COL11A1 decreased the expression of ERα and its downstream target genes. Overall, our findings suggest that overexpressed COL11A1 contributes to tamoxifen resistance, and targeting COL11A1 holds great promise for reversing endocrine resistance.

DOI: https://doi.org/10.1038/s41523-024-00645-3