bims-merabr 2025-02-02 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–02–02
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis.
Smurf2 Suppresses Proliferation and Cell Cycle of Triple-Negative Breast Cancer Cells by Promoting the Polyubiquitination and Degradation of RPL35A.
SGK3 promotes estrogen receptor-positive breast cancer proliferation by activating STAT3/ZMIZ2 pathway to stabilise β-catenin.
Investigation of ITGB3 Heterogeneity to Overcome Trastuzumab Resistance in HER2-Positive Breast Cancer.
Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis.
SHP2 promotes the epithelial-mesenchymal transition in triple negative breast cancer cells by regulating β-catenin.
Twist-Induced Epithelial-to-Mesenchymal Transition Confers Specific Metabolic and Mitochondrial Alterations.
Breast Cancer-Derived Extracellular Vesicles Modulate the Cytoplasmic and Cytoskeletal Dynamics of Blood-Brain Barrier Endothelial Cells.

Commun Biol. 2025 Jan 16. 8(1): 64

USP35 promotes the growth of ER positive breast cancer by inhibiting ferroptosis via BRD4-SLC7A11 axis.

Jiawei Cao, Tao Wu, Tong Zhou, Zewei Jiang, Yinrui Ren, Jiawei Yu, Jiayi Wang, Changrui Qian, Guang Wu, Licai He, Hongzhi Li, Rixu Lin, Min Liu, Haihua Gu.

Anti-estrogen endocrine therapies greatly improve survival of estrogen receptor positive (ER + ) breast cancer. Unfortunately, about 30% of patients do not respond to endocrine therapies initially. We previously showed that deubiquitinase USP35 and ERα act in a positive feedback loop to promote the carcinogenesis of ER+ breast cancer although it is unclear whether USP35 regulates cell death in ER+ breast cancer. In this study, we uncovered that USP35 inhibited ferroptosis of ER+ breast cancer cells. Mechanistically, USP35 interacted with, deubiquitinated, and stabilized BRD4. Consequentially, BRD4 mediated USP35-induced SLC7A11 upregulation, inhibiting ferroptosis and promoting the growth of ER+ breast cancer cells. Furthermore, BRD4 inhibitor (+)-JQ-1 inhibited USP35-enhanced tumorigenesis in vivo. Our findings demonstrated that the USP35-BRD4-SLC7A11 axis contributes to the growth of ER+ breast cancer by inhibiting ferroptosis. Targeting USP35 together with ferroptosis inducer may represent a potential promising strategy for treating ER+ breast cancer that does not respond to endocrine therapies.

DOI: https://doi.org/10.1038/s42003-025-07513-1
J Cell Mol Med. 2025 Jan;29(2): e70394

Smurf2 Suppresses Proliferation and Cell Cycle of Triple-Negative Breast Cancer Cells by Promoting the Polyubiquitination and Degradation of RPL35A.

Siyu Wei, Yuying Liu, Zhihao Wang, Ti Wei, Wenkai Zhou, Wanwan Li, Jiaxin Zhang, Zhiyi Liu, Zhao Liu.

  Human L35a ribosomal protein (RPL35A) has been reported to confer higher drug resistance and viability to triple-negative breast cancer (TNBC) cells, but the mechanism related to its promotion of TNBC malignant progression is still unclear. Here, we found that silencing of RPL35A could inhibit the proliferation of TNBC cells by suppressing the G1/S phase transition. Furthermore, SMAD-specific E3 ubiquitin protein ligase 2 (Smurf2) was found to be a potential upstream ubiquitin ligase of RPL35A. Smurf2 could interact with RPL35A and promote its degradation and K63-linked polyubiquitination, thereby suppressing the G1/S phase transition and proliferation of TNBC cells. In addition, the roles of Smurf2 were confirmed in a xenograft mouse model. Finally, we found a negative correlation between the protein levels of RPL35A and Smurf2 in human TNBC tissues. In summary, Smurf2 inhibits the proliferation of TNBC cells by blocking the cell cycle process, which is associated with regulating RPL35A.

Keywords:  L35a ribosomal protein; SMAD‐specific E3 ubiquitin protein ligase 2; proliferation and cell cycle; triple‐negative breast cancer; ubiquitination

DOI:  https://doi.org/10.1111/jcmm.70394
Br J Pharmacol. 2025 Jan 28.

SGK3 promotes estrogen receptor-positive breast cancer proliferation by activating STAT3/ZMIZ2 pathway to stabilise β-catenin.

Lie Yuan, Yongqing Cai, Gang Wang, Xu Liu, Bo Chen, Duanfang Zhou, Yuanli Wu, Na Qu, Xiaoli Li, Weiying Zhou.

   BACKGROUND AND PURPOSE: Breast cancer is a leading threat to women's health, with approximately 70% of cases being estrogen receptor-positive. SGK3 is regulated by estrogen and is positively associated with estrogen receptor expression, although its molecular role remains unclear.
EXPERIMENTAL APPROACH: Proteomics was used to identify SGK3's downstream targets. Tissue microarray immunofluorescence evaluated SGK3 and ZMIZ2 expression in ER+ breast cancer. Lentiviral-mediated knockdown and overexpression of SGK3 and/or ZMIZ2 assessed their effects on cell proliferation in vitro and in vivo. Chromatin immunoprecipitation (ChIP) analyzed p-STAT3 binding to the ZMIZ2 promoter, and Co-immunoprecipitation (Co-IP) examined ZMIZ2-β-catenin interaction.
KEY RESULTS: SGK3 expression was elevated in breast tumour tissues correlating with reduced patient survival. Proteomic analysis identified ZMIZ2 as a downstream target of SGK3. Overexpression of SGK3 promoted the proliferation of estrogen receptor-positive breast cancer in MCF-7 and T47D cells. Inhibition had the opposite effects. ZMIZ2 overexpression rescued the proliferation deficit in SGK3 knockdown cells. ZMIZ2 was found to bind and stabilises β-catenin. Knockdown of SGK3 led to β-catenin degradation via polyubiquitination, a process reversed by ZMIZ2 overexpression. STAT3 was identified as a downstream effector of SGK3 and its knockdown reduced cytoplasmic and nuclear p-STAT3 and STAT3, and inhibited ZMIZ2 and β-catenin expression. Celastrol suppressed estrogen receptor-positive breast cancer cell proliferation by inhibiting the SGK3/STAT3/ZMIZ2/β-catenin pathway.
CONCLUSIONS AND IMPLICATIONS: SGK3 expression is associated with poorer survival rates, thus SGK3 is a potential therapeutic target. As celastrol can inhibit SGK3 expression it could be an effective therapeutic agent.

Keywords:  SGK3; STAT3; ZMIZ2; cell proliferation; estrogen receptor‐positive; β‐catenin

DOI:  https://doi.org/10.1111/bph.17453
Biology (Basel). 2024 Dec 25. pii: 9. [Epub ahead of print]14(1):

Investigation of ITGB3 Heterogeneity to Overcome Trastuzumab Resistance in HER2-Positive Breast Cancer.

Asiye Busra Boz Er.

  HER2-positive breast cancer has an aggressive tumour progression among breast cancers characterized by the overexpression of HER2. Trastuzumab is an FDA-approved drug and has significantly improved outcomes for patients; however, drug resistance remains a major challenge. Tumour heterogeneity, describing genetic, epigenetic, and phenotypic differences within and between tumours, complicates tumour treatment and contributes to drug resistance. Understanding the mechanisms underlying Trastuzumab resistance, such as tumour heterogeneity, is crucial for developing new and effective therapeutic strategies. This study investigates the role of ITGB3 heterogeneity in Trastuzumab resistance, focusing on its impact on TGF-β signalling and migration marker response. It also evaluates the potential of combining Trastuzumab with the integrin β3 inhibitor cilengitide to overcome resistance associated with ITGB3 levels. Trastuzumab-resistant HER2-positive HCC1954 and SKBR3 breast cancer cell lines were generated and analysed for ITGB3 expression heterogeneity. The impact of ITGB3 on TGF-β-responsive genes (WWP1, CARM1, RASGRP1, THBS1, KCTD5, SGCA, EIF3S6, MCAM, FXR2, MTMR3, SOCS3, SLC2A4RG, MMP2, MMP9, and HSP47) and cell migration (Col4a1, fibronectin, ICAM1, Timp2, and vimentin) was analysed using luciferase reporter assays and real-time PCR. The effects of combined treatment with Trastuzumab and cilengitide were also evaluated via wound closure assay. ITGB3 expression varied significantly among resistant clones, correlating with increased expression of TGF-β-responsive genes and enhanced migration markers. Combined treatment with Trastuzumab and cilengitide significantly reduced TGF-β signalling and migration-related gene expression, particularly in high ITGB3-expressing cells. ITGB3 plays a critical role in Trastuzumab resistance through the modulation of TGF-β signalling, migration, and contributing to tumour heterogeneity. Targeting ITGβ3, alone or in combination with cilengitide, offers a promising strategy to resensitize resistant HER2-positive breast cancer cells to Trastuzumab. These findings provide valuable insights into the mechanisms of Trastuzumab resistance and suggest potential therapeutic avenues for improving patient outcomes.

Keywords:  HER2-positive breast cancer; ITGB3; TGF-β signalling; cilengitide; trastuzumab resistance; tumour heterogeneity

DOI:  https://doi.org/10.3390/biology14010009
Cancer Lett. 2025 Jan 23. pii: S0304-3835(25)00057-6. [Epub ahead of print]612 217493

Dual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis.

Xiaona You, Xi Hu, Zenghui Sun, Wenwen Xu, Lanlan Liu, Tao Huang, Shenli Yuan, Jilong Yin, Hao Wang, Limei Wang, Juncheng Wang, Wei Xu, Zhiyue Zhang, Yingjie Zhang, Yuchen Fan, Fabao Liu.

  Dysregulated lipid metabolism is linked to tumor progression. In this study, we identified Niemann-Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. In breast cancer cells, PKM2 knockout (KO) enhanced NPC1L1 expression while downregulating peroxisome proliferator-activated receptor α (PPARα) signaling pathway. PPARα and nuclear factor-E2 p45-related factor 1/2(Nrf1/2) are transcription factors regulating NPC1L1. In vitro PKM2 KO enhanced recruitment of Nrf1/2 to the NPC1L1 promoter region. Fenofibrate, a PPARα activator, promoted NPC1L1 expression; ezetimibe, an NPC1L1 inhibitor and effective Nrf2 activator, also elevated NPC1L1 expression. Combined administration of fenofibrate and ezetimibe significantly induced cytoplasmic vacuolation, and cell apoptosis. Mechanistically, this combined administration activated inositol required enzyme 1α(IRE1α) and produced the spliced form of X-box binding protein (XBP1s), which in turn enhanced lysine demethylase 6B (KDM6B) transcription. XBP1s interacts with KDM6B to activate genes involved in the unfolded protein response by demethylating di- and tri-methylated lysine 27 of histone H3 (H3K27), consequently increasing H3K27 acetylation levels in breast cancer cell lines. Fenofibrate and ezetimibe synergistically inhibited tumor growth in vivo. Our findings reveal that dual targeting of PPARα and NPC1L1 may represent a novel therapeutic regimen for breast cancer therapy.

Keywords:  Lipid metabolism; NPC1L1; PKM2; PPARα; Synergistic effect

DOI:  https://doi.org/10.1016/j.canlet.2025.217493
J Cancer Res Clin Oncol. 2025 Jan 29. 151(2): 55

SHP2 promotes the epithelial-mesenchymal transition in triple negative breast cancer cells by regulating β-catenin.

Shihan Qian, Jingjing Zhu, Qing Han, Huang Cheng, Huaibin Zhou.

   PURPOSE: Growing evidence suggests that the tyrosine phosphatase SHP2 is pivotal for tumor progression. Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, characterized by its high recurrence rate, aggressive metastasis, and resistance to chemotherapy. Understanding the mechanisms of tumorigenesis and the underlying molecular pathways in TNBC could aid in identifying new therapeutic targets.
METHODS: In this study, we conducted bioinformatics analysis of the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to examine PTPN11 (encoding SHP2) expression levels and perform survival analysis in TNBC. Additionally, we analyzed SHP2 levels in four TNBC cell lines and a normal breast epithelial cell line using Western blot. Furthermore, we knocked down SHP2 expression via RNA interference in three TNBC cell lines. To assess the impact of SHP2 on invasion and migration, we conducted transwell assays and wound healing experiments. An in vivo experiment utilizing a mouse xenograft model was also performed to evaluate tumor metastasis. Moreover, we detected the expression levels of epithelial-mesenchymal transition (EMT) biomarkers and investigated the mechanism between SHP2 and β-catenin using Western blot and immunofluorescence experiments.
RESULTS: We found that high SHP2 expression was associated with a poor prognosis in patients with TNBC. The migratory and invasive abilities of TNBC cells in vitro, as well as the metastatic potential of TNBC in mouse xenograft models, were reduced after SHP2 depletion. Downregulation of SHP2 also decreased the expression of mesenchymal markers but induced upregulation of the epithelial marker E-cadherin. Additionally, SHP2 promoted β-catenin stability by inhibiting its degradation via the proteasome. Furthermore, c-Myc expression and GSK3β and AKT phosphorylation, which are involved in β-catenin signaling, were decreased in SHP2-depleted TNBC cells.
CONCLUSION: Our study demonstrates that SHP2 is involved in migration, invasion, and EMT in TNBC cells by modulating β-catenin. Manipulating SHP2 expression or its target protein β-catenin may offer a novel approach to TNBC therapy.

Keywords:  AKT; Epithelial-mesenchymal transition; GSK3β; SHP2; Triple negative breast cancer; β-catenin

DOI:  https://doi.org/10.1007/s00432-025-06097-x
Cells. 2025 Jan 09. pii: 80. [Epub ahead of print]14(2):

Twist-Induced Epithelial-to-Mesenchymal Transition Confers Specific Metabolic and Mitochondrial Alterations.

Haleigh N Parker, Kayla L Haberman, Tolulope Ojo, Juli Watkins, Adhwaitha Nambiar, Kayla Morales, Bernd Zechmann, Joseph H Taube.

  Cells undergo significant epigenetic and phenotypic change during the epithelial-to-mesenchymal transition (EMT), a process observed in development, wound healing, and cancer metastasis. EMT confers several advantageous characteristics, including enhanced migration and invasion, resistance to cell death, and altered metabolism. In disease, these adaptations could be leveraged as therapeutic targets. Here, we analyze Twist-induced EMT in non-transformed HMLE cells as well as a breast cancer cell line with (MDA-MB-231) and without (MCF7) EMT features to compare differences in metabolic pathways and mitochondrial morphology. Analysis of oxidative and glycolytic metabolism reveals a general EMT-associated glycolytic metabolic phenotype accompanied by increased ATP production. Furthermore, a decrease in mitochondrial size was also associated with EMT-positive cells. However, mitochondrial elongation and spatial dynamics were not consistently altered, as HMLE Twist cells exhibit more rounded and dispersed mitochondria compared to control, while MDA-MB-231 cells exhibit more elongated and clustered mitochondria compared to MCF7 cells. These results provide further insight as to the contextual nature of EMT conferred properties.

Keywords:  EMT; TNBC; metabolism; mitochondria

DOI:  https://doi.org/10.3390/cells14020080
J Extracell Vesicles. 2025 Jan;14(1): e70038

Breast Cancer-Derived Extracellular Vesicles Modulate the Cytoplasmic and Cytoskeletal Dynamics of Blood-Brain Barrier Endothelial Cells.

Sara Busatto, Tzu-Hsi Song, Hyung Joon Kim, Caleb Hallinan, Michael N Lombardo, Anat O Stemmer-Rachamimov, Kwonmoo Lee, Marsha A Moses.

  Extracellular vesicles (EVs) from brain-seeking breast cancer cells (Br-EVs) breach the blood-brain barrier (BBB) via transcytosis and promote brain metastasis. Here, we defined the mechanisms by which Br-EVs modulate brain endothelial cell (BEC) dynamics to facilitate their BBB transcytosis. BEC treated with Br-EVs show significant downregulation of Rab11fip2, known to promote vesicle recycling to the plasma membrane and significant upregulation of Rab11fip3 and Rab11fip5, which support structural stability of the endosomal compartment and facilitate vesicle recycling and transcytosis, respectively. Using machine learning and quantitative global proteomic, we identified novel Br-EV-induced changes in BECs morphology, motility, and proteome that correlate with decreased BEC cytoplasm and cytoskeletal organization and dynamics. These results define early steps leading to breast-to-brain metastasis and identify molecules that could serve as targets for therapeutic strategies for brain metastasis.

Keywords:  blood‐brain barrier; brain metastasis; breast cancer; exosomes; extracellular vesicles; microvesicles; pre‐metastatic niche

DOI:  https://doi.org/10.1002/jev2.70038