bims-merabr 2025-06-01 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–06–01
seven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis.
DEC1 promotes breast cancer bone metastasis through transcriptional activation of CXCR4.
TRIM29 upregulation contributes to chemoresistance in triple negative breast cancer via modulating S100P-β-catenin axis.
17β-Estradiol Promotes Tumorigenicity Through an Autocrine AREG/EGFR Loop in ER-α-Positive Breast Cancer Cells.
Tumor-secreted TNF induces NCoA3 upregulation in breast cancer-associated adipocytes via TNFR1/NF-κB signaling.
The correlation between obesity and the occurrence and development of breast cancer.
Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights.

Sci Rep. 2025 May 25. 15(1): 18172

Targeting of the IL-33/Wnt axis restricts breast cancer stemness and metastasis.

Guanglin Fan, Shuting Zuo, Zhen Wang, Siwei Zhang, Liping Liu, Haoge Luo, Yingdong Xie, Yan Zhang, Dong Li.

  Interleukin-33 (IL-33) plays multifaceted roles in tumor progression, but its autocrine regulation of breast cancer stemness and metastasis via the Wnt pathway remains unclear. Here, we investigated the IL-33/ST2 axis in breast cancer using CRISPR/Cas9, single-cell RNA sequencing, and murine models (orthotopic 4T1 and spontaneous MMTV-PyMT). Elevated IL-33 levels correlated with aggressive subtypes and poor prognosis. IL-33 overexpression enhanced proliferation, migration, and cancer stem cell (CSC) marker expression (CD44, ALDH1) in 4T1 and MDA-MB-231 cells, whereas ST2 knockdown via CRISPR or adeno-associated virus (AAV) attenuated tumor growth and metastasis in vivo, reducing CSC frequency. Mechanistically, IL-33 activated Wnt/β-catenin signaling to promote stemness, which was reversed by the Wnt inhibitor XAV-939. Single-cell analysis revealed that IL-33 overexpression skewed the immune microenvironment toward immunosuppression, while ST2 knockdown restored antitumor immunity. Our findings establish an IL-33-Wnt axis as a critical driver of breast cancer aggressiveness and propose AAV-mediated ST2 silencing as a novel therapeutic strategy. Targeting this axis may offer dual benefits by suppressing stemness and enhancing immune surveillance, warranting clinical exploration for advanced breast cancer.

Keywords:  Breast cancer stem cells; IL-33; Immunotherapy; ST2 knockdown; Wnt pathway

DOI:  https://doi.org/10.1038/s41598-025-03260-9
J Biomed Res. 2025 May 25. 1-22

DEC1 promotes breast cancer bone metastasis through transcriptional activation of CXCR4.

Ying Huo, Kaiao Chen, Zhiyi Qiang, Lan Lin, Wei Liu, Jian Yang.

  Bone metastasis is the primary cause of mortality in breast cancer (BC) patients. This study elucidates the functional role of DEC1 (differentiated embryonic chondrocyte expressed gene 1) in promoting BC bone metastasis. Analysis of patient-derived samples and public databases revealed significant upregulation of DEC1 and CXCR4 in breast tumors compared to adjacent normal tissues, with elevated levels correlating with increased metastatic potential, suggesting their synergistic involvement in BC progression. Intracardiac injection experiments demonstrated that 4T1-WT cells induced more severe osteolysis and larger metastatic lesions than 4T1-DEC1-KD cells. In MDA-MB-231 cells, DEC1 overexpression (OE) upregulated CXCR4 and proliferation/migration-related genes, whereas DEC1 knockdown (KD) suppressed these effects. Notably, AMD3100 (a CXCR4 antagonist) partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes. Mechanistically, DEC1 was found to bind the CXCR4 promoter region (-230 to -326) and activate its transcription, corroborated by ChIP-seq data. Furthermore, pharmacological inhibition of AKT (LY294002) or JAK2 (AZD1480), but not ERK (PD98059), attenuated DEC1-mediated CXCR4 upregulation, although all three inhibitors mitigated DEC1-driven migration-related gene expression. Additionally, DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts, amplifying the CXCR4/CXCL12 axis within the bone microenvironment. Collectively, our findings demonstrate that DEC1 promotes breast cancer (BC) bone metastasis by directly transactivating CXCR4 expression, providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.

Keywords:  CXCR4; breast cancer (BC) bone metastasis; differentiated embryonic chondrocyte expressed gene 1

DOI:  https://doi.org/10.7555/JBR.39.20250031
Cell Commun Signal. 2025 May 26. 23(1): 244

TRIM29 upregulation contributes to chemoresistance in triple negative breast cancer via modulating S100P-β-catenin axis.

Qitong Wu, Sumit Siddharth, Deepak Verma, Sheetal Parida, Dipali Sharma.

Triple negative breast cancer, an inherently aggressive disease, is further impaired by the limited therapeutic options and chemotherapy-resistance; hence, elucidating the signaling nodes underlying chemotherapy resistance is of major interest. Focusing on the differentially expressed genes in recurrent TNBC, we identified TRIM29, a ubiquitin ligase belonging to TRIM family, as a uniquely enriched protein in chemoresistant TNBC. Here, we demonstrate that chemoresistant TNBC cells are inherently aggressive, exhibiting elevated growth and migration potential compared to chemosensitive cells, and in particular, they possess higher TRIM29 expression whose expression level modulation results in altered chemosensitivity. TRIM29 overexpression reduces chemotherapy response whereas TRIM29 knockout not only increases chemosensitivity but also reduces TNBC tumor growth. Tumor-dissociated cells maintain TRIM29 knockout status as well as exhibit similar functional alterations as chemoresistant TNBC cells. Mechanistically, RNA-sequencing of parental-chemosensitive, chemoresistant-inherently overexpressing TRIM29 and chemoresistant-TRIM29 knockout TNBC cells reveals a unique set of genes (S100P, SERPINB3, SERPINB4, CEACAM5, CEACAM6 and CDH6) showing significant upregulation with the acquisition of chemoresistance and downregulation with the TRIM29 knockout. Furthermore, an enrichment of β-catenin pathway in chemoresistant TNBC cells is observed. We uncovered a functional network where S100P, a metastasis inducing secretory factor, bidirectionally interacts with TRIM29, and modulates the expression of SERPINB3, SERPINB4, CEACAM5, CEACAM6 as well as β-catenin pathway genes. Showing the functional importance, S100P inhibitor reduces the growth and mammosphere formation in chemoresistant TNBC. Moreover, combining β-catenin inhibitor with chemotherapy shows synergistic inhibition of chemoresistant TNBC cells. Indeed, higher expression of TRIM29, S100P and β-catenin associates with reduced recurrence free survival. This work proposes TRIM29 as an important node that modulates a unique gene network in chemoresistant TNBC and whose biological impact is mediated by modulation of S100P and β-catenin.

DOI: https://doi.org/10.1186/s12964-025-02233-9
Cells. 2025 05 12. pii: 703. [Epub ahead of print]14(10):

17β-Estradiol Promotes Tumorigenicity Through an Autocrine AREG/EGFR Loop in ER-α-Positive Breast Cancer Cells.

Sun Young Yoon, Yisun Jeong, Jai Min Ryu, Se Kyung Lee, Byung Joo Chae, Jonghan Yu, Seok Won Kim, Seok Jin Nam, Sangmin Kim, Jeong Eon Lee.

  We previously reported that the level of EGFR expression is directly associated with the survival rate of estrogen receptor-positive (ER+) breast cancer patients. Here, we investigated how ER activation by 17β-estradiol (E2), the most potent form of estrogen, affects the expression or activity of EGFR or EGFR-related genes in ER+ breast cancer cells. As expected, E2 enhanced cell proliferation, the induction of S phase, and tumor growth in ER+ breast cancer models. E2 also increased the expression of secretory proteins, including amphiregulin (AREG), angiogenin, artemin, and CXCL16. We focused on AREG, which is a ligand of the epidermal growth factor receptor (EGFR). The levels of AREG expression were positively correlated with ESR1 expression. Our results also showed higher AREG mRNA expression levels in ER+ breast cancer cells than in ER- breast cancer cells. We treated ER+ breast cancer cells with lapatinib to inhibit the AREG/EGFR signaling pathway and then completely inhibited E2-induced cell proliferation and S-phase induction. Similar to the lapatinib treatment, cell proliferation, S-phase induction, cell migration, and tumor growth were suppressed by AREG knockdown. Taken together, we demonstrated that the induction of AREG by E2 contributes to EGFR activation, which then affects cell proliferation and tumor growth. Therefore, we suggest that AREG acts as an intermediary between EGFR and ER and targeting both ERs and EGFRs through combination therapy could prevent tumor progression in EGFR+ ER+ breast cancer patients.

Keywords:  AREG; EGFR; ER; prognosis; targeted therapy

DOI:  https://doi.org/10.3390/cells14100703
Biochim Biophys Acta Mol Basis Dis. 2025 May 28. pii: S0925-4439(25)00279-0. [Epub ahead of print] 167931

Tumor-secreted TNF induces NCoA3 upregulation in breast cancer-associated adipocytes via TNFR1/NF-κB signaling.

María Cecilia Lira, Francisco D Rosa, Juliana Lourdes Bernacchia, Alejandra G Palma, Natalia Paladino, Mónica A Costas, María Fernanda Rubio.

  In breast cancer, adipocytes are the predominant cell type in the microenvironment, and the continuous communication between these tissues alters the adipose phenotype. However, molecular mechanisms promoting these changes are still poorly understood. Previously, we demonstrated that NCoA3 expression is increased in adipose tissue adjacent to breast cancer and that this increase is associated with an inflammatory profile. This study aimed to investigate the mechanisms underlying NCoA3 expression in adipocytes within the breast tumor microenvironment. We demonstrated that breast cancer-secreted TNF increases NCoA3 expression in adipocytes, and this upregulation is dependent on NF-κB transcriptional activity. Furthermore, the use of a TNF blocker prevented both coactivator overexpression and macrophages recruitment, mimicking the effects observed when NCoA3 expression was downregulated using a short hairpin RNA. These findings shed light on the molecular mechanisms by which breast cancer cells modulate adipocyte behavior, identifying NCoA3 as a key mediator in the tumor-adipose tissue crosstalk. Targeting this pathway through TNF inhibition offers promising therapeutic strategy to attenuate tumor-associated inflammation and potentially improve outcomes in breast cancer patients.

Keywords:  Breast cancer; Inflammation; Mammary adipose tissue; NF-κB; Nuclear receptor coactivator 3

DOI:  https://doi.org/10.1016/j.bbadis.2025.167931
Eur J Med Res. 2025 May 26. 30(1): 419

The correlation between obesity and the occurrence and development of breast cancer.

Jun-Jie Hu, Qi-Yue Zhang, Zhi-Chun Yang.

  This study reviews the mechanisms by which obesity affects the development and progression of breast cancer (BC). The association between obesity and BC is mainly due to three aspects: disruption of glycolipid metabolism, abnormal cell function and imbalance of adipokine levels. The dysregulation of glycolipid metabolism caused by obesity, including the accumulation of cholesterol and fatty acids and the reprogramming of glucose metabolism, promotes the growth and invasion of tumour cells. Obesity triggers multiple cellular abnormalities, particularly in lipid-associated macrophages and cancer-associated adipocytes, which promote tumour progression and immunosuppression by secreting inflammatory factors and various fatty acids into the tumour microenvironment. Obesity leads to an imbalance in the expression of several adipokines. Leptin upregulation is closely associated with BC metastasis and resistance to endocrine therapy, while reduced adiponectin levels attenuate the protective effect. At the same time, chronic inflammation and insulin resistance not only further increase the risk of BC, but also exacerbate tumour resistance. In terms of treatment, weight-loss drugs and metformin can improve the efficacy of obesity-related BC treatment to some extent. Intervention strategies targeting adipose tissue remodelling, lipid metabolism and leptin regulation also show potential clinical value, but more research is needed to clarify their safety and efficacy. This review provides systematic ideas and references for research into the mechanisms and clinical management of obesity-related BC.

Keywords:  Adipocyte; Adipokine; Breast cancer; Inflammatory; Metabolic disorders; Obesity; Tumour microenvironment

DOI:  https://doi.org/10.1186/s40001-025-02659-4
Cancer Metab. 2025 May 29. 13(1): 26

Oncogenic role of fumarate hydratase in breast cancer: metabolic reprogramming and mechanistic insights.

Shyng-Shiou F Yuan, Anupama Vadhan, Hieu D H Nguyen, Pang-Yu Chen, Chih-Huang Tseng, Ching-Hu Wu, Yu-Chieh Chen, Yi-Chia Wu, Stephen Chu-Sung Hu, Steven Lo, Ming-Feng Hou, Yen-Yun Wang.

Breast cancer remains the most prevalent malignancy among women globally, with its complexity linked to genetic variations and metabolic alterations within tumor cells. This study investigates the role of fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, in breast cancer progression. Our findings reveal that FH mRNA and protein levels are significantly upregulated in breast cancer tissues and correlate with poor patient prognosis and aggressive tumor characteristics. Using in vitro and in vivo models, we demonstrate that FH overexpression enhances breast cancer cell proliferation, migration, and invasion through metabolic reprogramming and by increasing reactive oxygen species (ROS) production. Furthermore, we identify matrix metalloproteinase 1 (MMP1) as a downstream effector of FH, linked to p21 downregulation, elucidating a novel regulatory pathway influencing tumor behavior. Interestingly, unlike its tumor-suppressing role in other cancer types, this study highlights FH's oncogenic potential in breast cancer. Our results suggest that FH enhances cancer cell viability and aggressiveness via both catalytic and non-catalytic mechanisms. This work not only underscores the metabolic adaptations of breast cancer cells but also proposes FH as a potential biomarker and therapeutic target for breast cancer management.

DOI: https://doi.org/10.1186/s40170-025-00397-z