bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒06‒16
twenty-two papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.
  2. TEX19 increases the levels of CDK4 and promotes breast cancer by disrupting SKP2-mediated CDK4 ubiquitination.
  3. UM171 suppresses breast cancer progression by inducing KLF2.
  4. Single-cell analysis of tumor microenvironment and cell adhesion reveals that interleukin-1 beta promotes cancer cell proliferation in breast cancer.
  5. Loss of ADAR1 induces ferroptosis of breast cancer cells.
  6. An essential gene signature of breast cancer metastasis reveals targetable pathways.
  7. Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway.
  8. SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer.
  9. The crosstalk between metabolic reprogramming and epithelial-mesenchymal transition and their synergistic roles in distant metastasis in breast cancer.
  10. Blockage of TMEM189 induces G2/M arrest and inhibits the growth of breast tumors.
  11. Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.
  12. Dual Inhibition of the TrkA and JAK2 pathways using Entrectinib and Pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers.
  13. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
  14. TPD52 is a prognostic biomarker and potential therapeutic target for ER+/PR+/HER2+ breast cancer.
  15. DAB2IP inhibits glucose uptake by modulating HIF-1α ubiquitination under hypoxia in breast cancer.
  16. RET overexpression leads to increased brain metastatic competency in luminal breast cancer.
  17. Blockade of tumor cell-intrinsic PD-L1 signaling enhances AURKA-targeted therapy in triple negative breast cancer.
  18. Targeting fatty acid synthase in preclinical models of TNBC brain metastases synergizes with SN-38 and impairs invasion.
  19. Knockdown of Glycolysis-Related LINC01070 Inhibits the Progression of Breast Cancer.
  20. miR-181c-5p/DERL1 pathway controls breast cancer progression mediated by TRAF6-linked K63 ubiquitination of AKT.
  21. ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Estrogen Receptor Positive Breast Cancer.
  22. Deciphering the TCF19/miR-199a-5p/SP1/LOXL2 pathway: Implications for breast cancer metastasis and epithelial-mesenchymal transition.
  1. J Exp Clin Cancer Res. 2024 Jun 11. 43(1): 163
    BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.
    Sushmitha Sriramulu, Shivani Thoidingjam, Wei-Min Chen, Oudai Hassan, Farzan Siddiqui, Stephen L Brown, Benjamin Movsas, Michael D Green, Anthony J Davis, Corey Speers, Eleanor Walker, Shyam Nyati.
      BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment.METHODS: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays.
    RESULTS: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t1/2, ~8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade.
    CONCLUSIONS: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.
    Keywords:  BUB1; DNA damage response; DNAPK; NHEJ; Radiation sensitization; TNBC
    DOI:  https://doi.org/10.1186/s13046-024-03086-9
  2. Cancer Cell Int. 2024 Jun 12. 24(1): 207
    TEX19 increases the levels of CDK4 and promotes breast cancer by disrupting SKP2-mediated CDK4 ubiquitination.
    Huantao Liu, He Wang, Hongyu Zhang, Miaomiao Yu, Yu Tang.
      BACKGROUND: Globally, breast cancer in women is the fifth leading cause of cancer death. There is an urgent need to explore the molecular mechanism of breast cancer proliferation and metastasis.METHOD: TCGA database analysis was used to analyze genes expression in breast cancer and normal samples and the association between gene expression and prognosis. Immunohistochemical staining, qPCR and western blotting was sued to detected gene expression. The cell function tests were conducted to investigate the effects of TEX19 and CDK4 with abnormal expression on cell proliferation, migration, apoptosis, cell cycle, and colony formation. Bioinformatics analysis methods combined with CHX tracking experiment and Co-IP experiment were performed to screen and verify the downstream molecule and regulatory mechanism of TEX19. Besides, subcutaneous tumorigenesis model in nude mice was constructed.
    RESULTS: TEX19 was significantly upregulated in breast cancer, and the TEX19 level was related to tumor invasion and prognosis. TEX19 knockdown inhibited the proliferation and migration of breast cancer cells, increased cell apoptosis, and blocked the cell cycle in the G2 phase. Besides, TEX19 suppressed the growth of tumors in the body. Mechanically, TEX19 upregulated the level of CDK4 protein, which depended on the E3 ubiquitin ligase SKP2. Specifically, TEX19 knockdown and SKP2 protein overexpression destroyed the stability of CDK4 protein and enhanced the ubiquitination of CDK4 protein. Additionally, CDK4 knockdown inhibited the proliferation, migration, and colony formation of breast cancer cells, and alleviated the promotion of TEX19 overexpression on the proliferation and migration of breast cancer cell.
    CONCLUSION: TEX19 and CDK4 were upregulated in breast cancer, and TEX19 increased the level of CDK4 protein by influencing SKP2-mediated ubiquitination of CDK4, thereby promoting the progression of breast cancer.
    Keywords:  Breast cancer; CDK4; TEX19; Ubiquitination
    DOI:  https://doi.org/10.1186/s12935-024-03384-4
  3. Breast Cancer Res Treat. 2024 Jun 14.
    UM171 suppresses breast cancer progression by inducing KLF2.
    Xiaojuan Ran, Anling Hu, Yi Kuang, Chunlin Wang, Wuling Liu, Xiao Xiao, Eldad Zacksenhaus, Xiangdi Yu, Yaacov Ben-David.
      PURPOSE: Breast cancer is the most frequent cancer in women with significant death rate. Morbidity is associated with drug resistance and metastasis. Development of novel drugs is unmet need. The aim of this study is to show potent anti-neoplastic activity of the UM171 compound on breast cancer cells and its mechanism of action.METHODS: The inhibitory effect of UM171 on several breast cancer (BC) cell lines was examined using MTT and colony-forming assays. Cell cycle and apoptosis assays were utilized to determine the effect of UM171 on BC cell proliferation and survival. Wound healing scratch and transwell migration assays were used to examine the migration of BC cell lines in culture. Xenograft of mouse model with 4T1 cells was used to determine inhibitory effect of UM171 in vivo. Q-RT-PCR and western blotting were used to determine the expression level of genes effected by UM171. Lentivirus-mediated shRNAs were used to knockdown the expression of KLF2 in BC cells.
    RESULTS: UM171 was previously identified as a potent agonist of human hematopoietic stem cell renewal and inhibitor of leukemia. In this study, UM171 was shown to inhibit the growth of multiple breast cancer cell lines in culture. UM171-mediated growth inhibition was associated with the induction of apoptosis, G2/M cell cycle arrest, lower colony-forming capacity, and reduced motility. In a xenotransplantation model of mouse triple-negative breast cancer 4T1 cells injected into syngeneic BALB/c mice, UM171 strongly inhibited tumor growth at a level comparable to control paclitaxel. UM171 increased the expression of the three PIM genes (PIM1-3) in breast cancer cells. Moreover, UM171 strongly induced the expression of the tumor suppressor gene KLF2 and cell cycle inhibitor P21CIP1. Accordingly, knockdown of KLF2 using lentivirus-mediated shRNA significantly attenuated the growth suppressor activity of UM171. As PIM1-3 act as oncogenes and are involved in breast cancer progression, induction of these kinases likely impedes the inhibitory effect of KLF2 induction by UM171. Accordingly, combination of UM171 with a PAN-PIM inhibitor LGH447 significantly reduced tumor growth in culture.
    CONCLUSION: These results suggested that UM171 inhibited breast cancer progression in part through activation of KLF2 and P21. Combination of UM171 with a PAN-PIM inhibitor offer a novel therapy for aggressive forms of breast cancer.
    Keywords:  Breast cancer; KLF2; P21; PIM1-PIM3 activation; Proliferation; UM171
    DOI:  https://doi.org/10.1007/s10549-024-07372-0
  4. Animal Model Exp Med. 2024 Jun 11.
    Single-cell analysis of tumor microenvironment and cell adhesion reveals that interleukin-1 beta promotes cancer cell proliferation in breast cancer.
    Wenyan Wang, Gehong Dong, Ziguo Yang, Shaoxiang Li, Jia Li, Lin Wang, Qiang Zhu, Yuchen Wang.
      BACKGROUND: Triple-negative breast cancer (TNBC), which is so called because of the lack of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) receptors on the cancer cells, accounts for 10%-15% of all breast cancers. The heterogeneity of the tumor microenvironment is high. However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood.METHODS: We analyzed single-cell RNA sequencing data from five HER2 positive, 12 ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry.
    RESULTS: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2-integrin-aLb2 complex, and then release interleukin 1 beta (IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth.
    CONCLUSION: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.
    Keywords:  IL1B; biomaterial; breast cancer; plasma cells; scRNA‐seq
    DOI:  https://doi.org/10.1002/ame2.12445
  5. Cell Signal. 2024 Jun 10. pii: S0898-6568(24)00226-2. [Epub ahead of print]121 111258
    Loss of ADAR1 induces ferroptosis of breast cancer cells.
    Chuan Yin, Meng-Meng Zhang, Guo-Liang Wang, Xiao-Yan Deng, Zeng Tu, Shan-Shan Jiang, Zheng-Dan Gao, Meng Hao, Yong Chen, Yi Li, Sheng-Yong Yang.
      Adenosine deaminases acting on RNA 1(ADAR1), an RNA editing enzyme that converts adenosine to inosine by deamination in double-stranded RNAs, plays an important role in occurrence and progression of various types of cancer. Ferroptosis has emerged as a hot topic of cancer research in recent years. We have previously reported that ADAR1 promotes breast cancer progression by regulating miR-335-5p and METTL3. However, whether ADAR1 has effects on ferroptosis in breast cancer cells is largely unknown. In this study, we knocked down ADAR1 using CRISPR-Cas9 technology or over-expressed ADAR1 protein using plasmid expressing ADAR1 in MCF-7 and MDA-MB-231 breast cancer cell lines, then detected cell viability, and levels of ROS, MDA, GSH, Fe2+, GPX4 protein and miR-335-5p. We showed that the cell proliferation was inhibited, levels of ROS, MDA, Fe2+, and miR-335-5p were increased, while GSH and GPX4 levels were decreased after loss of ADAR1, compared to the control group. The opposite effects were observed after ADAR1 overexpression in the cells. Further, we demonstrated that ADAR1-controlled miR-335-5p targeted Sp1 transcription factor of GPX4, a known ferroptosis molecular marker, leading to inhibition of ferroptosis by ADAR1 in breast cancer cells. Moreover, RNA editing activity of ADAR1 is not essential for inducing ferroptosis. Collectively, loss of ADAR1 induces ferroptosis in breast cancer cells by regulating miR-335-5p/Sp1/GPX4 pathway. The findings may provide insights into the mechanism by which ADAR1 promotes breast cancer progression via inhibiting ferroptosis.
    Keywords:  ADAR1; Breast cancer cell; Ferroptosis; GPX4; miR-335-5p
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111258
  6. Breast Cancer Res. 2024 Jun 12. 26(1): 98
    An essential gene signature of breast cancer metastasis reveals targetable pathways.
    Yiqun Zhang, Fengju Chen, Marija Balic, Chad J Creighton.
      BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology.METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes higher in metastasis for genes essential for breast cancer proliferation, we incorporated CRISPR-based data from breast cancer cell lines.
    RESULTS: A significant fraction of genes with higher expression in metastasis versus paired primary were essential by CRISPR. These 264 genes represented an essential signature of breast cancer metastasis. In contrast, nonessential metastasis genes largely involved tumor biopsy site. The essential signature predicted breast cancer patient outcome based on primary tumor expression patterns. Pathways underlying the essential signature included proteasome degradation, the electron transport chain, oxidative phosphorylation, and cancer metabolic reprogramming. Transcription factors MYC, MAX, HDAC3, and HCFC1 each bound significant fractions of essential genes.
    CONCLUSIONS: Associations involving the essential gene signature of breast cancer metastasis indicate true biological changes intrinsic to cancer cells, with important implications for applying existing therapies or developing alternate therapeutic approaches.
    DOI:  https://doi.org/10.1186/s13058-024-01855-0
  7. Chem Biol Drug Des. 2024 Jun;103(6): e14559
    Silencing PCMT1 enhances the sensitivity of breast cancer cells to paclitaxel through the PI3K/Akt/STMN1 pathway.
    Ke Zhang, Jin-You Li, Kai Li.
      This study aimed to investigate whether silencing Protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) expression can enhance the sensitivity of breast cancer cells to paclitaxel and its possible mechanism. Tumor tissues and adjacent histologically normal tissues were collected from patients with breast cancer admitted to our hospital. Human normal breast epithelial cells MCF10A, human breast cancer cells MCF-7, and paclitaxel-resistant breast cancer cells MCF-7/PR were purchased. MCF-7/PR cells were further grouped into negative control (NC) group, si-PCMT1 group (transfected with si-PCMT1), 740Y-P group (treated with 740Y-P, an activator of phosphatidylinositol 3-kinase (PI3K)/ v-Akt Murine Thymoma Viral Oncogene (AKT) signaling pathway), and si-PCMT1 + 740Y-P group (transfected with si-PCMT1 and then treated with 740Y-P). The expression level of PCMT1 in tissues and cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot analysis was used to detect the protein expression level of PCMT1 in tissues and cells as well as the protein level of p-PI3K, PI3K, p-Akt, Akt, and Stathmin1 (STMN1) in cells. 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and colony formation assays were used to determine cell viability, scratch assay was used to assess the migration ability of cells, and Transwell assay was used to assess the invasion ability of cells. The expression of PCMT1 was remarkably up-regulated in breast cancer tissues and MCF-7/PR cells. Silencing PCMT1 expression significantly inhibited the proliferation, migration, and invasion of MCF-7/PR cells, and alleviated the resistance of cancer cells to paclitaxel. Additionally, silencing PCMT1 expression also inhibited the activation of PI3K/Akt/STMN1 pathway in MCF-7/PR cells, while activating PI3K/Akt/STMN1 pathway significantly reversed the effect of silencing PCMT1 expression on MCF-7/PR cells. PCMT1 is highly expressed in breast cancer tissues and MCF-7/PR cells, and silencing PCMT1 expression can not only inhibit the development of breast cancer but also enhance paclitaxel sensitivity. Its mechanism of action may be achieved by inhibiting PI3K/Akt/STMN1 signaling.
    Keywords:  PCMT1; PI3K/Akt/STMN1; breast cancer; paclitaxel
    DOI:  https://doi.org/10.1111/cbdd.14559
  8. Biochem Biophys Res Commun. 2024 Jun 04. pii: S0006-291X(24)00759-9. [Epub ahead of print]724 150223
    SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer.
    Zhaoran Sun, Zhongkun Wang, Yirao Zhang, Xue Li, Hanchi Zhou, Simin Shao, Haowei Cao, Hao Liu, Daoyong Zhang.
      SWI/SNF chromatin remodeling complexes play a key role in gene transcription as epigenetic regulators and are typically considered to act as tumor suppressors in cancers. Compared to other cancer-related components of the SWI/SNF complex, research on SMARCC2, a component of the initial BAF core, has been relatively limited. This study aimed to elucidate the role of SMARCC2 in breast cancer by employing various in vitro and in vivo methods including cell proliferation assays, mammosphere formation, and xenograft models, complemented by RNA-seq, ATAC-seq, and ChIP analyses. The results showed that SMARCC2 silencing surprisingly led to the suppression of breast tumorigenesis, indicating a pro-tumorigenic function for SMARCC2 in breast cancer, which contrasts with the roles of other SWI/SNF subunits. In addition, SMARCC2 depletion reduces cancer stem cell features of breast cancer cells. Mechanistic study showed that SMARCC2 silencing downregulated the oncogenic Ras-PI3K signaling pathway, likely by directly regulating the chromatin accessibility of the enhancers of the key genes such as PIK3CB. Together, these results expand our understanding of the SWI/SNF complex's role in cancer development and identify SMARCC2 as a promising new target for breast cancer therapies.
    Keywords:  Cancer stem cell; Chromatin accessibility; PI3K; SMARCC2; SWI/SNF
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150223
  9. Medicine (Baltimore). 2024 Jun 14. 103(24): e38462
    The crosstalk between metabolic reprogramming and epithelial-mesenchymal transition and their synergistic roles in distant metastasis in breast cancer.
    Liyan Yu, Yongni Chen, Yingyu Chen, Kangwei Luo.
      BACKGROUND: Metabolic reprogramming (MR) and epithelial-mesenchymal transition (EMT) are crucial phenomena involved in the distant metastasis of breast cancer (BRCA). This study aims to assess the risk of distant metastasis in BRCA patients based on MR and EMT processes and investigate their underlying mechanisms.METHODS: Gene sets related to EMT and MR were downloaded. MR-related genes (MRG) and EMT-related genes (ERG) were obtained. Principal Component Analysis method was used to define the EMT Potential Index (EPI) and MR Potential Index (MPI) to quantify the EMT and MR levels in each tumor tissue. A linear scoring model, the Metastasis Score, was derived using the union of MRGs and ERGs to evaluate the risk of distant metastasis/recurrence in BRCA. The Metastasis Score was then validated in multiple datasets. Additionally, our study explored the underlying mechanism of the Metastasis Score and its association with tumor immunity, focusing on HPRT1 gene expression in breast cancer tissues of transfer and untransferred groups using experimental methods.
    RESULTS: A total of 59 MRGs and 30 ERGs were identified in the present study. Stratifying the dataset based on EPI and MPI revealed significantly lower survival rates (P < .05) in the MPI_high and EPI_high groups. Kaplan-Meier analysis indicated the lowest survival rate in the EPI-high + MPI-high group. The Metastasis Score demonstrated its ability to distinguish prognoses in GSE2034, GSE17705, and TCGA-BRCA datasets. Additionally, differences in mutated genes were found between the high- and the low-Metastasis Score groups, displaying significant associations with immune cell infiltration and anti-tumor immune status. Notably, the 13 genes included in the Metastasis Score showed a strong association with prognosis and tumor immunity. Immunohistochemistry and western blot results revealed high expression of the HPRT1 gene in the transfer group.
    CONCLUSION: This study established the Metastasis Score as a reliable tool for evaluating the risk of distant metastasis/recurrence in BRCA patients. Additionally, we identified key genes involved in MR and EMT crosstalk, offering valuable insights into their roles in tumor immunity and other relevant aspects.
    DOI:  https://doi.org/10.1097/MD.0000000000038462
  10. Biochem Biophys Rep. 2024 Jul;38 101744
    Blockage of TMEM189 induces G2/M arrest and inhibits the growth of breast tumors.
    Song Chen, Meng Tie, Mengyue Wu, Anyuan He, Yali Chen.
      Cancer is the major cause of premature death in humans worldwide, demanding more efficient therapeutics. Aberrant cell proliferation resulting from the loss of cell cycle regulation is the major hallmark of cancer, so targeting cell cycle is a promising strategy to combat cancer. However, the molecular mechanism underlying the dysregulation of cell cycle of cancer cells remains poorly understood. TMEM189, a newly identified protein, plays roles in the biosynthesis of ethanolamine plasmalogen and the regulation of autophagy. Here, we demonstrated that the expression level of TMEM189 was negatively correlated with the survival rate of the cancer patients. TMEM189 deficiency significantly suppresses the cancer cell proliferation and migration, and causes cell cycle G2/M arrest both in vitro and in vivo. Furthermore, TMEM189 depletion suppressed the growth of breast tumors in vivo. Taken together, our work indicated that TMEM189 promotes cancer progression by regulating cell cycle G2/M transition, suggesting that it is a promising target in cancer therapy.
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101744
  11. J Exp Clin Cancer Res. 2024 Jun 14. 43(1): 166
    Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.
    Vitale Del Vecchio, Ayesha Rehman, Sameer Kumar Panda, Martina Torsiello, Martina Marigliano, Maria Maddalena Nicoletti, Giuseppe Andrea Ferraro, Vincenzo De Falco, Rosamaria Lappano, Eva Lieto, Francesca Pagliuca, Carlo Caputo, Marcella La Noce, Gianpaolo Papaccio, Virginia Tirino, Nirmal Robinson, Vincenzo Desiderio, Federica Papaccio.
      BACKGROUND: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes.METHODS: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis.
    RESULTS: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring.
    CONCLUSIONS: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.
    Keywords:  Adipose Stem cells; Breast Cancer; Mitoception; Mitochondrial transfer; Multi-drug resistance; Tunneling nanotubes
    DOI:  https://doi.org/10.1186/s13046-024-03087-8
  12. Cancer Lett. 2024 Jun 07. pii: S0304-3835(24)00417-8. [Epub ahead of print] 217023
    Dual Inhibition of the TrkA and JAK2 pathways using Entrectinib and Pacritinib suppresses the growth and metastasis of HER2-positive and triple-negative breast cancers.
    Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo.
      HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.
    Keywords:  JAK2; TrkA; breast cancer; breast cancer metastasis; combined targeted therapy
    DOI:  https://doi.org/10.1016/j.canlet.2024.217023
  13. Nature. 2024 Jun 12.
    Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
    Jackie E Bader, Melissa M Wolf, Gian Luca Lupica-Tondo, Matthew Z Madden, Bradley I Reinfeld, Emily N Arner, Emma S Hathaway, KayLee K Steiner, Gabriel A Needle, Zaid Hatem, Madelyn D Landis, Eden E Faneuff, Amondrea Blackman, Elysa M Wolf, Matthew A Cottam, Xiang Ye, Madison E Bates, Kyra Smart, Wenjun Wang, Laura V Pinheiro, Anthos Christofides, DuPreez Smith, Vassiliki A Boussiotis, Scott M Haake, Kathryn E Beckermann, Kathryn E Wellen, Cynthia A Reinhart-King, C Henrique Serezani, Cheng-Han Lee, Christa Aubrey, Heidi Chen, W Kimryn Rathmell, Alyssa H Hasty, Jeffrey C Rathmell.
      Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
    DOI:  https://doi.org/10.1038/s41586-024-07529-3
  14. Chin Clin Oncol. 2024 Jun 01. pii: cco-23-156. [Epub ahead of print]
    TPD52 is a prognostic biomarker and potential therapeutic target for ER+/PR+/HER2+ breast cancer.
    Xiaolin Cheng, Zhengdong Li, Xiaoqing Jia, Zhiyuan Fan, Qizhi He, Zhigang Zhuang.
      BACKGROUND: Breast cancer (BRCA) represents a significant health challenge for women globally, with refractory cases showing resistance to current therapeutic strategies. The discovery of novel molecular markers and therapeutic targets is critical for improving outcomes in these patients. The primary aim of this study is to elucidate the role of tumor protein D52 (TPD52) as a novel molecular marker and potential therapeutic target to improve outcomes for BRCA patients.METHODS: Using bioinformatics methods, we screened and evaluated the expression, prognosis, and associated mechanisms of TPD52 in BRCA. Two hundred and thirty-eight BRCA cases and 19 control cases were collected from Shanghai First Maternity and Infant Hospital, and the protein expression of TPD52 was detected by immunohistochemistry, and the correlation between TPD52 and the prognosis of BRCA was analyzed.
    RESULTS: The expression of TPD52 in BRCA tissues was significantly higher than that in the control (P<0.001), displaying a strong association with key clinical variables, concurrently indicating an unfavorable prognostic implication. The survival analysis revealed high TPD52 expression was an independent adverse prognostic factor for overall (P=0.008) and disease-specific survival (P=0.005). Gene set enrichment analysis showed that TPD52 negatively correlated with estradiol, AMP-activated protein kinase, and other responses. Immune infiltration analysis showed that TPD52 was associated with immune cell infiltration, Th-1/Th-2 cell balance, and immune defense cells such as dendritic and plasmacytoid dendritic cells. It is further found that high TPD52 expression is associated with progression-free and disease-free survival from the analysis of immunohistochemical data of the patients at our hospital.
    CONCLUSIONS: In summary, TPD52 may serve as an independent prognostic biomarker for BRCA, which may represent a promising novel therapeutic target, particularly for the refractory estrogen receptor-positive (ER+ )/progesterone receptor-positive (PR+ )/human epidermal growth factor receptor 2-positive (HER2+ ) BRCA cases that have failed endocrine therapy and targeted treatment.
    Keywords:  Tumor protein D52 (TPD52); biomarker; breast cancer (BRCA)
    DOI:  https://doi.org/10.21037/cco-23-156
  15. Oncogenesis. 2024 Jun 11. 13(1): 20
    DAB2IP inhibits glucose uptake by modulating HIF-1α ubiquitination under hypoxia in breast cancer.
    Hongliang Dong, Weiyi Jia, Weijian Meng, Rui Zhang, Zhihong Qi, Zhuo Chen, Sophia Xie, Jiang Min, Liang Liu, Jie Shen.
      Metabolic reprogramming has become increasingly important in tumor biology research. The glucose metabolic pathway is a major energy source and is often dysregulated in breast cancer. DAB2IP is widely reported to be a tumor suppressor that acts as a scaffold protein to suppress tumor malignancy in breast cancer. Interestingly, DAB2IP has also been found to be a potential regulator of glucose uptake; however, the exact mechanism remains unclear. In this study, we found that DAB2IP inhibited glucose uptake under hypoxia conditions in breast cancer cells by suppressing HIF-1α signals. Mechanically, DAB2IP interacted with the E3 ubiquitin ligase STUB1 via its PER domain, thus triggering STUB1 mediated HIF-1α ubiquitylation and degradation, and inhibit glucose metabolism and tumor progression. Deleting the PER domain abrogated the DAB2IP-related inhibitory effects on glucose uptake, intracellular ATP production, and lactic acid production in breast cancer cells. These findings elucidate the biological roles of DAB2IP in cancer-related glucose metabolism as well as a novel mechanism by which STUB1-driven HIF-1α ubiquitylated degradation is regulated in breast cancer.
    DOI:  https://doi.org/10.1038/s41389-024-00523-4
  16. J Natl Cancer Inst. 2024 Jun 10. pii: djae091. [Epub ahead of print]
    RET overexpression leads to increased brain metastatic competency in luminal breast cancer.
    Petra Jagust, Aoibhin M Powell, Mihaela Ola, Louise Watson, Ana de Pablos-Aragoneses, Pedro García-Gómez, Ramón Fallon, Fiona Bane, Mona Heiland, Gareth Morris, Brenton Cavanagh, Jason McGrath, Daniela Ottaviani, Aisling Hegarty, Sinéad Cocchiglia, Kieron J Sweeney, Stephen MacNally, Francesca M Brett, Jane Cryan, Alan Beausang, Patrick Morris, Manuel Valiente, Arnold D K Hill, Damir Varešlija, Leonie S Young.
      BACKGROUND: Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor.METHODS: RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action.
    RESULTS: A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor-positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo, RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro-brain metastatic phenotype.
    CONCLUSION: Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases.
    DOI:  https://doi.org/10.1093/jnci/djae091
  17. Front Oncol. 2024 ;14 1384277
    Blockade of tumor cell-intrinsic PD-L1 signaling enhances AURKA-targeted therapy in triple negative breast cancer.
    Andrew Takchi, Minzhi Zhang, Mohammad Jalalirad, Roberto Leon Ferre, Royal Shrestha, Tufia Haddad, Jann Sarkaria, Ann Tuma, Jodi Carter, Hillman David, Karthik Giridhar, Liewei Wang, Carol Lange, Urban Lendahl, James Ingle, Matthew Goetz, Antonino Bonaventura D'Assoro.
      Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and mainly affects pre-menopausal and minority women. Because of the lack of ER, PR or HER2 expression in TNBC, there are limited options for tailored therapies. While TNBCs respond initially to standard of care chemotherapy, tumor recurrence commonly occurs within 1 to 3 years post-chemotherapy and is associated with early organ metastasis and a high incidence of mortality. One of the major mechanisms responsible for drug resistance and emergence of organ metastasis is activation of epithelial to mesenchymal transition (EMT) reprogramming. EMT-mediated cancer cell plasticity also promotes the enrichment of cancer cells with a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype [cancer stem cells (CSCs)], characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance, immune evasion and metastasis. In this study we demonstrate for the first time a positive feedback loop between AURKA and intra-tumoral PD-L1 oncogenic pathways in TNBC. Genetic targeting of intra-tumoral PD-L1 expression impairs the enrichment of ALDHhigh CSCs and enhances the therapeutic efficacy of AURKA-targeted therapy. Moreover, dual AURKA and PD-L1 pharmacological blockade resulted in the strongest inhibition of tumor growth and organ metastatic burden. Taken together, our findings provide a compelling preclinical rationale for the development of novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis in patients with advanced TNBC.
    Keywords:  cancer cell plasticity; immunotherapy; organ metastases; small molecule inhibitor; triple negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2024.1384277
  18. NPJ Breast Cancer. 2024 Jun 10. 10(1): 43
    Targeting fatty acid synthase in preclinical models of TNBC brain metastases synergizes with SN-38 and impairs invasion.
    Habib A Serhan, Liwei Bao, Xu Cheng, Zhaoping Qin, Chia-Jen Liu, Jason A Heth, Aaron M Udager, Matthew B Soellner, Sofia D Merajver, Aki Morikawa, Nathan M Merrill.
      Fatty acid synthesis (FAS) has been shown to play a key role in the survival of brain-metastatic (BM) breast cancer. We demonstrate that the fatty acid synthase inhibitor TVB-2640 synergizes with the topoisomerase inhibitor SN-38 in triple-negative breast cancer (TNBC) BM cell lines, upregulates FAS and downregulates cell cycle progression gene expression, and slows the motility of TNBC BM cell lines. The combination of SN-38 and TVB-2640 warrants further consideration as a potential therapeutic option in TNBC BMs.
    DOI:  https://doi.org/10.1038/s41523-024-00656-0
  19. Cureus. 2024 May;16(5): e60093
    Knockdown of Glycolysis-Related LINC01070 Inhibits the Progression of Breast Cancer.
    Qiang Hu, Yiduo Wang, Weipu Mao.
      Accumulative evidence confirms that glycolysis and long non-coding RNAs (lncRNAs) are closely associated with tumor development. The aim of this study was to construct a novel prognostic model based on glycolysis-related lncRNAs (GRLs) in breast cancer patients. By performing Pearson correlation analysis and Lasso regression analysis on differentially expressed genes and lncRNAs associated with glycolysis in the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) datasets, we identified nine GRLs and constructed associated prognostic risk signature. Kaplan-Meier survival analysis and univariate and multivariate Cox analysis showed that patients in the low-risk group had a better prognosis. The receiver operator characteristics (ROC) curves showed that the area under the curve (AUC) of the prognostic risk signature predicting patients' overall survival at 1-, 3- and 5- years was 0.78, 0.71, and 0.71, respectively. Moreover, the validation curves also showed that the signature had better diagnostic efficacy and clinical predictive power. Furthermore, clone formation assay, EdU assay, and Transwell assay showed that knockdown of LINC01070 inhibited breast cancer progression. We developed a prognostic risk-associated GRLs signature that can accurately predict the breast cancer patient's prognostic status, and LINC01070 can be used as a potential biomarker for the prognosis of breast cancer patients.
    Keywords:  breast cancer; glycolysis; linc01070; lncrnas; nomogram; risk model
    DOI:  https://doi.org/10.7759/cureus.60093
  20. Cancer Cell Int. 2024 Jun 10. 24(1): 204
    miR-181c-5p/DERL1 pathway controls breast cancer progression mediated by TRAF6-linked K63 ubiquitination of AKT.
    Yang Bai, Zhanqiang Zhang, Jiong Bi, Qian Tang, Keying Jiang, Chen Yao, Wenjian Wang.
      BACKGROUND: Aberrant Derlin-1 (DERL1) expression is associated with an overactivation of p-AKT, whose involvement in breast cancer (BRCA) development has been widely speculated. However, the precise mechanism that links DERL1 expression and AKT activation is less well-studied.METHODS: Bioinformatic analyses hold a promising approach by which to detect genes' expression levels and their association with disease prognoses in patients. In the present work, a dual-luciferase assay was employed to investigate the relationship between DERL1 expression and the candidate miRNA by both in vitro and in vivo methods. Further in-depth studies involving immunoprecipitation-mass spectrum (IP-MS), co-immunoprecipitation (Co-IP), as well as Zdock prediction were performed.
    RESULTS: Overexpression of DERL1 was detected in all phenotypes of BRCA, and its knockdown showed an inhibitory effect on BRCA cells both in vitro and in vivo. The Cancer Genome Atlas (TCGA) database reported that DERL1 overexpression was correlated with poor overall survival in BRCA cases, and so the quantification of DERL1 expression could be a potential marker for the clinical diagnosis of BRCA. On the other hand, miR-181c-5p was downregulated in BRCA, suggesting that its overexpression could be a potent therapeutic route to improve the overall survival of BRCA cases. Prior bioinformatic analyses indicated a somewhat positive correlation between DERL1 and TRAF6 as well as between TRAF6 and AKT, but not between miR-181c-5p and DERL1. In retrospect, DERL1 overexpression promoted p-AKT activation through K63 ubiquitination. DERL1 was believed to directly interact with the E3 ligase TRAF6. As Tyr77Ala or Tyr77Ala/Gln81Ala/Arg85Ala/Val158Ala attempts to prevent the interaction between DERL1 and TRAF domain of TRAF6, resulted in a significant reduction in K63-ubiquitinated p-AKT production. However, mutations in Gln81Ala, Arg85Ala, or Val158Ala could possibly interrupt with these processes.
    CONCLUSIONS: Our data confirm that mediation of the miR-181c-5p/DERL1 pathway by TRAF6-linked AKT K63 ubiquitination holds one of the clues to set our focus on toward meeting the therapeutic goals of BRCA.
    Keywords:  Breast cancer; DERL1; K63-ubiquitination; Micro RNA; Prognosis
    DOI:  https://doi.org/10.1186/s12935-024-03395-1
  21. Pathobiology. 2024 Jun 11.
    ATF4 as a Prognostic Marker and Modulator of Glutamine Metabolism in Estrogen Receptor Positive Breast Cancer.
    Roshni Patel, Lutfi H Alfarsi, Rokaya El-Ansari, Brendah K Masisi, Busra Erkan, Ali Fakroun, Ian O Ellis, Emad A Rakha, Andrew R Green.
      PURPOSE: ATF4, a stress-responsive transcription factor that upregulates adaptive genes, is a potential prognostic marker and modulator of glutamine metabolism in breast cancer. However, its exact role remains to be elucidated.METHODS: ATF4 expression was evaluated at genomic and transcriptomic levels using METABRIC (n=1980), GeneMiner (n=4712) and KM-Plotter datasets. Proteomic expression was assessed via immunohistochemistry (n=2225) in the Nottingham Primary Breast Carcinoma Series. ATF4 genomic copy number (CN) variation and mRNA/protein in association with clinicopathological parameters, amino acid transporters (AATs), and patient outcome was investigated.
    RESULTS: Genomic, transcriptomic, and proteomic overexpression of ATF4 was associated with more aggressive ER-negative tumours. ATF4 mRNA and protein expression were significantly associated with increased expression of glutamine related AATs including SLC1A5 (p&lt;0.01) and SLC7A11 (p&lt;0.02). High ATF4 and SLC1A5 protein expression was significantly associated with shorter breast cancer-specific survival (p&lt;0.01), especially in ER+ tumours (p&lt;0.01), while high ATF4 and SLC7A11 protein expression was associated with shorter survival (p&lt;0.01).
    CONCLUSION: These findings suggest a complex interplay between ATF4 and AATs in breast cancer biology and underscore the potential role for ATF4 as a prognostic marker in ER+ breast cancer, offering a unique opportunity for risk stratification and personalised treatment strategies.
    DOI:  https://doi.org/10.1159/000539564
  22. Cancer Lett. 2024 Jun 06. pii: S0304-3835(24)00389-6. [Epub ahead of print]597 216995
    Deciphering the TCF19/miR-199a-5p/SP1/LOXL2 pathway: Implications for breast cancer metastasis and epithelial-mesenchymal transition.
    Shu-Yu Li, Nan Zhang, Hao Zhang, Ning Wang, Ya-Ying Du, Han-Ning Li, Chen-Shen Huang, Xing-Rui Li.
      Globally, breast cancer (BC) is the predominant malignancy with a significant death rate due to metastasis. The epithelial-mesenchymal transition (EMT) is a fundamental initiator for metastatic progression. Through advanced computational strategies, TCF19 was identified as a critical EMT-associated gene with diagnostic and prognostic significance in BC, based on a novel EMT score. Molecular details and the pro-EMT impact of the TCF19/miR-199a-5p/SP1/LOXL2 axis were explored in BC cell lines through in vitro validations, and the oncogenic and metastatic potential of TCF19 and LOXL2 were investigated using subcutaneous and tail-vein models. Additionally, BC-specific enrichment of TCF19 and LOXL2 was measured using a distribution landscape driven by diverse genomic analysis techniques. Molecular pathways revealed that TCF19-induced LOXL2 amplification facilitated migratory, invasive, and EMT activities of BC cells in vitro, and promoted the growth and metastatic establishment of xenografts in vivo. TCF19 decreases the expression of miR-199a-5p and alters the nuclear dynamics of SP1, modulating SP1's affinity for the LOXL2 promoter, leading to increased LOXL2 expression and more malignant characteristics in BC cells. These findings unveil a novel EMT-inducing pathway, the TCF19/miR-199a-5P/SP1/LOXL2 axis, highlighting the pivotal role of TCF19 and suggesting potential for novel therapeutic approaches for more focused BC interventions.
    Keywords:  Breast cancer; Computational strategies; Epithelial-mesenchymal transition; Metastasis; TCF19/miR-199a-5P/SP1/LOXL2 axis
    DOI:  https://doi.org/10.1016/j.canlet.2024.216995
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