bims-merabr 2025-03-30 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–03–30
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Nidogen-1 suppresses cell proliferation, migration, and glycolysis via integrin β1-mediated HIF-1α downregulation in triple-negative breast cancer.
ZBTB6 promotes breast cancer progression by inhibiting ARHGAP6 transcription and modulating the STAT3 signaling pathway.
GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance.
ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.
TSPAN31 Activates Fatty Acid Metabolism and PI3K/AKT Pathway to Promote Tumor Progression in Breast Cancer.
Breast cancer extracellular matrix invasion depends on local mechanical loading of the collagen network.

Sci Rep. 2025 Mar 27. 15(1): 10633

Nidogen-1 suppresses cell proliferation, migration, and glycolysis via integrin β1-mediated HIF-1α downregulation in triple-negative breast cancer.

Joo-Hyung Lee, Seogho Son, Yunhyo Ko, Hogeun Lim, Minhyeok Lee, Min-Gyeong Kang, Hyungjoo Kim, Kyung-Min Lee, Incheol Shin.

  Nidogen-1 (NID1) is a secreted glycoprotein widely distributed in basement membranes. NID1 interacts with extracellular matrix proteins such as collagen and laminin and has been implicated in the progression of various cancers. However, study on the role of NID1 in breast cancer is scarce and inconsistent. In this work, we found that the expression of NID1 is significantly lower in breast cancer tissue than in normal tissue. In addition, NID1 expression correlated negatively with a poor prognosis for breast cancer patients. Based on those findings, we speculated that NID1 might act as a cancer suppressor in breast cancer. To investigate the role of NID1 in breast cancer, we constructed NID1-overexpressing cell lines. NID1 overexpression decreased breast cancer cell proliferation, migration, and in vivo tumor growth. Moreover, glucose metabolism, which is known to enhance cancer cell proliferation and migration, was also decreased by NID1 overexpression. Mechanistically, NID1 overexpression downregulated hypoxia-inducible factor-1α (HIF-1α) expression at the transcription level. Furthermore, we found that NID1 reduced integrin β1 stability and downregulated the transcription of HIF-1α through the FAK/Src/NF-κB p65 signaling axis, which is downstream of integrin β1. Together, the results of this study demonstrate the tumor suppressive role of NID1 in triple-negative breast cancer.

Keywords:  Breast cancer; Glycolysis; HIF1α; NID1; TNBC

DOI:  https://doi.org/10.1038/s41598-024-84880-5
J Transl Med. 2025 Mar 25. 23(1): 370

ZBTB6 promotes breast cancer progression by inhibiting ARHGAP6 transcription and modulating the STAT3 signaling pathway.

Xiaojiang Tang, Chaowei Deng, Yang Liu, Shengyu Pu, Qi Zheng, Yudong Zhou, Na Hao.

   BACKGROUND: The ZBTB (zinc finger and BTB domain-containing) protein family comprises a significant class of transcription factors that interact with various corepressors and histone/protein-modifying enzymes. This interaction facilitates chromatin remodeling and the regulation of gene silencing or activation, thereby playing a crucial role in cancer progression. However, the biological effects and molecular mechanisms of ZBTB6, a member of the ZBTB family, in cancer remain unclear.
METHODS: The expression levels of ZBTB6 in breast cancer (BC) were investigated through public database queries, real-time quantitative PCR (qRT‒PCR), and Western blot analysis. The effects of ZBTB6 on BC cell viability were assessed via MTT assays. Flow cytometry was utilized to analyze the cell cycle distribution and apoptosis. Additionally, cell-derived xenograft experiments were conducted to study the impact of ZBTB6 on BC growth in vivo. The relationship between ZBTB6 and the ARHGAP6 promoter was evaluated via bioinformatics predictions, chromatin immunoprecipitation (ChIP) coupled with qRT‒PCR, and luciferase reporter assays.
RESULTS: Our study demonstrated that ZBTB6 is highly expressed in primary BC specimens and cell lines and strongly correlated with tumor grade and poor prognosis. In vitro, ZBTB6 knockdown inhibited cell viability and cell cycle progression while promoting apoptosis; conversely, ZBTB6 overexpression elicited the opposite effects. In vivo, the inhibition of ZBTB6 expression in BC cells significantly suppressed tumor growth. Furthermore, we identified ARHGAP6 as a transcriptional target downstream of ZBTB6, with ZBTB6 binding to the promoter region of ARHGAP6 to repress its transcription. Notably, ARHGAP6 can exert an inhibitory effect on tumors by attenuating STAT3 activity. Our results indicate that ZBTB6 overexpression enhances the STAT3 signaling pathway, whereas ARHGAP6 overexpression counteracts the effects of ZBTB6 overexpression in BC cells.
CONCLUSION: These findings suggest that ZBTB6 promotes breast cancer progression by repressing the transcription of ARHGAP6 and activating the STAT3 signaling pathway. Consequently, ZBTB6 may serve as a potential prognostic biomarker or therapeutic target for breast cancer patients.

Keywords:  ARHGAP6; Apoptosis; Breast cancer; Cell cycle; STAT3 signaling pathway; ZBTB6

DOI:  https://doi.org/10.1186/s12967-025-06364-y
Cells. 2025 Mar 08. pii: 398. [Epub ahead of print]14(6):

GATAD2B O-GlcNAcylation Regulates Breast Cancer Stem-like Potential and Drug Resistance.

Giang Le Minh, Jessica Merzy, Emily M Esquea, Nusaiba N Ahmed, Riley G Young, Ryan J Sharp, Tejsi T Dhameliya, Bernice Agana, Mi-Hye Lee, Jennifer R Bethard, Susana Comte-Walters, Lauren E Ball, Mauricio J Reginato.

  The growth of breast tumors is driven and controlled by a subpopulation of cancer cells resembling adult stem cells, which are called cancer stem-like cells (CSCs). In breast cancer, the function and maintenance of CSCs are influenced by protein O-GlcNAcylation and the enzyme responsible for this post-translational modification, O-GlcNAc transferase (OGT). However, the mechanism of CSCs regulation by OGT and O-GlcNAc cycling in breast cancer is still unclear. Analysis of the proteome and O-GlcNAcome, revealed GATAD2B, a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, as a substrate regulated by OGT. Reducing GATAD2B genetically impairs mammosphere formation, decreases expression of self-renewal factors and CSCs population. O-GlcNAcylation of GATAD2B at the C-terminus protects GATAD2B from ubiquitination and proteasomal degradation in breast cancer cells. We identify ITCH as a novel E3 ligase for GATAD2B and show that targeting ITCH genetically increases GATAD2B levels and increases CSCs phenotypes. Lastly, we show that overexpression of wild-type GATAD2B, but not the mutant lacking C-terminal O-GlcNAc sites, promotes mammosphere formation, expression of CSCs factors and drug resistance. Together, we identify a key role of GATAD2B and ITCH in regulating CSCs in breast cancer and GATAD2B O-GlcNAcylation as a mechanism regulating breast cancer stem-like populations and promoting chemoresistance.

Keywords:  GATAD2B; NuRD; O-GlcNAc; OGT; cancer; cancer stem cell; chemoresistance; signaling

DOI:  https://doi.org/10.3390/cells14060398
Cell Death Dis. 2025 Mar 25. 16(1): 201

ATP6AP1 promotes cell proliferation and tamoxifen resistance in luminal breast cancer by inducing autophagy.

Zhengwei Yan, Aidi Huang, Dongwen Ma, Chenao Hong, Shengmiao Zhang, Luling He, Hai Rao, Shiwen Luo.

Autophagy is a highly conserved cellular process essential for maintaining cellular homeostasis and influencing cancer development. Lysosomal acidification and autophagosome-lysosome fusion are two important steps of autophagy degradation that are tightly regulated. Although many key proteins that regulate these two events have been identified, the effector proteins that co-regulate both steps remain to be explored. ATP6AP1, an accessory subunit of V-ATPase, plays a critical role in the assembly and regulation of V-ATPase. However, the function of ATP6AP1 in autophagy remains unknown, and the role of ATP6AP1 in cancer is still poorly understood. In this study, we found that ATP6AP1 is overexpressed in luminal breast cancer tissues and promotes the proliferation and tamoxifen resistance of luminal breast cancer cells both in vitro and in vivo. We also observed that high ATP6AP1 expression correlates with poor overall patient survival. Our research further revealed that ATP6AP1 enhances tamoxifen resistance by activating autophagy. Mechanistically, ATP6AP1 promotes autophagy by regulating both lysosomal acidification and autophagosome-lysosome fusion. Remarkably, ATP6AP1 induces lysosomal acidification through the regulation of V-ATPase assembly and facilitates autophagosome-lysosome fusion by enhancing the interaction between Rab7 and the HOPS complex. Together, our studies identify ATP6AP1 as a crucial regulator of autophagy, potentially serving as a valuable prognostic marker or therapeutic target in human luminal breast cancer.

DOI: https://doi.org/10.1038/s41419-025-07534-y
Mol Carcinog. 2025 Mar 26.

TSPAN31 Activates Fatty Acid Metabolism and PI3K/AKT Pathway to Promote Tumor Progression in Breast Cancer.

Wenquan Luo, Yuxiang Sun, Liang Cao.

  Breast cancer (BC) is one of the most common human malignancies, but the mechanisms of BC have not been fully elucidated. Recently, tetraspanin 31 (TSPAN31) is reported to be linked to cancer progression. However, the function of TSPAN31 remains unclear in BC. Investigation of the function and potential mechanism of TSPAN31 in BC was the purpose of this study. Immunohistochemistry, western blot, and quantitative real-time polymerase chain reaction were applied to measure TSPAN31 expression. Loss and gain functional experiments were utilized to survey the influences of TSPAN31 on BC biological process, including cell growth, invasion, migration, and fatty acid metabolism. Mechanistically, Kyoto Encyclopedia of Genes and Genomes analysis based on DepMap database and Gene Set Enrichment Analysis based on The Cancer Genome Atlas database were executed to find TSPAN31-related pathway. Western blot was carried out to assess the changes of fatty acid synthase (FASN), sterol regulatory element binding protein 1 (SREBP1), acyl-CoA synthetase long-chain family member 1 (ACSL1), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-PI3K, protein kinase B (AKT), and p-AKT. In human non-triple negative breast cancer tissues and cells, TSPAN31 expression was upregulated. TSPAN31 knockdown induced BC cell apoptosis, inhibited cell proliferation, invasion, migration, and fatty acid metabolism, and reduced the protein levels of FASN, SREBP1, ACSL1, p-PI3K/PI3K, and p-AKT/AKT. In contrast, TSPAN31 overexpression led to the opposite results. Additionally, the activator of PI3K (740 Y-P) attenuated the inhibition of TSPAN31 knockdown on fatty acid metabolism, proliferation, and invasion in BC cells. Through activation of fatty acid metabolism and PI3K/AKT pathway, TSPAN31 played a carcinogenic role in BC. For the mechanism of BC tumorigenesis, our study provides an interesting insight.

Keywords:  PI3K/AKT pathway; TSPAN31; breast cancer; cell proliferation; fatty acid metabolism

DOI:  https://doi.org/10.1002/mc.23912
J Mater Chem B. 2025 Mar 26.

Breast cancer extracellular matrix invasion depends on local mechanical loading of the collagen network.

Hanadi M Alqosiri, Hadeel M Alqasiri, Sara E Alqasire, Victor E Nava, Bidhan C Bandyopadhyay, Christopher B Raub.

Active mechanical stresses in and around tumors affect cancer cell behavior and independently regulate cancer progression. To investigate the role of mechanical stress in breast cancer cell invasion, magnetic alginate beads loaded with iron oxide nanoparticles were coated with MDA-MB-231 breast cancer cells and embedded in a three-dimensional extracellular matrix (ECM) model subjected to an external magnetic field during culture. Bead displacement, cell shape and patterns of invasion of the collagen gel, and cell proliferation were assessed over 7 days of culture. The alginate beads swelled over the first 24 h in culture, creating circumferential stress akin to that created by tumor growth, while bead magnetic properties enabled local mechanical loading (compression, tension, and relaxation) and motion within the in vitro tissue constructs upon exposure to an external magnetic field. Beads displaced 0.2-1.6 mm through the collagen gels, depending on magnet size and distance, compressing the collagen network microstructure without gel mechanical failure. Invading cells formed a spatulate pattern as they moved into the compressed ECM region, with individual cells aligned parallel to the bead surface. During the first 24 hours of compressive magnetic force loading, invading cancer cells became round, losing elongation and ability to invade out from the bead surface, while still actively dividing. In contrast, cell invasion in unloaded constructs and in loaded constructs away from the compression region invaded as single cells, transversely outward from the bead surface. Finally, cell proliferation was 1.3× higher only after external magnet removal, which caused relaxation of mechanical stress in the collagen network. These findings indicate effects on breast cancer invasion of mechanical loading of ECM, both from compressive loading and from load relaxation. Findings point to the influence of mechanical stress on cancer cell behavior and suggest that relaxing mechanical stress in and around a tumor may promote cancer progression through higher proliferation and invasion.

DOI: https://doi.org/10.1039/d4tb01474j