bims-merabr 2025-10-12 papers

Int J Oncol. 2025 Dec;pii: 100. [Epub ahead of print]67(6):

Adipocyte‑derived extracellular vesicles sustain mitochondrial metabolism in breast cancer cells: New insights into the cross‑talk between cancer cells and the tumor microenvironment.

Luca Gelsomino, Piercarlo Del Console, Maria Stella Murfuni, Marco Gaspari, Francesca Giordano, Giuseppina Daniela Naimo, Marco Fiorillo, Grazia Arpino, Mario Giuliano, Salvatore Panza, Daniela Bonofiglio, Sebastiano Andò, Ines Barone, Cinzia Giordano, Stefania Catalano.

Adipocytes represent the most prominent component of breast tissue stroma and are recognized as significant contributors to the observed association between obesity and breast cancer (BC). It has been widely reported that dysfunctional adipose tissue in obesity has a profound effect on the biology of BC via the secretion of several bioactive molecules. Recently, extracellular vesicles (EVs), a heterogeneous group of membrane‑enclosed structures, have been recognized as key players in adipocyte‑BC cell communication. We previously demonstrated that adipocyte‑derived EVs promoted BC proliferation, migration, invasion, stemness and traits of epithelial‑to‑mesenchymal transition through the activation of hypoxia inducible factor‑1α (HIF‑1α). The present study, to further understand the impact of EVs in breast adiponcosis, investigated the effects of adipocyte‑derived EVs on the BC proteome. By employing liquid chromatography‑tandem mass spectrometry and different bioinformatic tools (such as Proteomap, STRING, FunRich, Reactome and MsigDB), it was found that adipocyte‑derived EVs regulated the expression of multiple proteins implicated in metabolic processes. Adipocyte‑derived EVs shifted cell metabolism towards oxidative phosphorylation in estrogen receptor‑positive (ER+) BC cell lines, including MCF‑7, ZR‑75‑1 and BT‑474 BC cells, through an increased mitochondrial activity along with an enhanced ATP production. These findings were extended by treating BC cells with EVs isolated from the serum of patients with BC classified as normal weight (NW‑EVs) and overweight or obese (OW/Ob‑EVs). Treatment of BC cells with OW/Ob‑EVs resulted in a significant increase of mitochondrial activity and ATP production compared with NW‑EVs. Of note, inhibition of HIF‑1α expression/activity reversed the effects of both adipocyte‑derived EVs and OW/Ob‑EVs on BC cell metabolism. In conclusion, the present study underscored the pivotal role of EVs in the BC‑obesity link, highlighting their involvement in driving metabolic reprogramming in ER+ BC cells through HIF‑1α.

Keywords: breast cancer; extracellular vesicles; hypoxia‑inducible factor 1; metabolism; obesity; oxidative phosphorylation

DOI: https://doi.org/10.3892/ijo.2025.5806

Cell Rep. 2025 Oct 07. pii: S2211-1247(25)01171-4. [Epub ahead of print]44(10): 116400

YEATS4 reads histone crotonylation to promote fatty acid metabolism and cancer cell stemness.

Zijun Peng, Huajing Yu, Yizhou Wang, Dan Zhao, Hangwei Fa, Leyi Qin, Yilei Ma, Mengyang Geng, Yuqing Wu, Ge Wu, Xin Wu, Chengying Zhang, Yue Wang, Jianying Liu, Haitao Li, Zhimin Lu, Yongfeng Shang, Jing Liang.

How histone lysine crotonylation (Kcr) is read and interpreted remains to be elucidated. We report here that YEATS4, a potential breast cancer driver identified recently by two independent genome-wide association studies, is a reader of H3K14cr. Integrative metabolomic, epigenomic, and transcriptomic analyses reveal that H3K14cr reading by YEATS4 is associated with a shift of cellular metabolic profile and transcription activation of a cohort of genes, including CD36, CPT1A, and ACOX1, that are critically involved in the uptake and metabolism of fatty acids. High expression of YEATS4 fortifies fatty acid metabolism, enhances self-renewal and growth of ALDH+ breast cancer stem cells, and is correlated with poor prognosis of breast cancer patients, especially the ER+ subtype. Our work uncovers YEATS4 as an "amplifier" in the feedforward circuit of histone crotonylation and lipid metabolism underlying the stemness and cell proliferation, supporting the pursuit of YEATS4 as a potential target for breast cancer intervention.

Keywords: CP: Cancer; CP: Molecular biology; YEATS4; breast cancer stemness; fatty acid metabolism; histone crotonylation

DOI: https://doi.org/10.1016/j.celrep.2025.116400

Cancer Gene Ther. 2025 Oct 10.

GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation.

Ruyue Xu, Jiahui Liang, Shuyuan Zhang, Puseletso Moru, Kainan Liao, Deping Xu, Guodong Cao, Chunlin Cai, Dandan Zang, Guoling Zhou, Min Ren, Haisheng Zhou.

Breast cancer is a leading cause of cancer-related death in women, and the development of effective treatments for advanced disease remains a critical challenge. Metastasis, the spread of cancer cells to distant sites, is the major cause of mortality in breast cancer. We identified a novel role for the G protein-coupled receptor 107 (GPR107) in promoting breast cancer invasion and metastasis. Furthermore, we found that GPR107 mediates a reduction in collagen Ⅳ (COL4), a key component of the extracellular matrix (ECM) that normally restricts tumor cell invasion. This reduction in COL4 levels was associated with GPR107 mediating the Clathrin-mediated endocytosis of COL4 from the ECM, an increase in matrix metalloproteinase 2 (MMP2) production to degrade COL4 in the ECM, and a decrease in COL4 production. Mechanistically, we identified GPR107 as a key mediator of the ERK/STAT3 pathway activation through β-arrestin, leading to increased expression of MMP2 and suppression of COL4 gene transcription, effectively promoting invasion and metastasis in breast cancer cells. These findings suggest that GPR107 could serve as a promising biomarker for predicting breast cancer malignancy and a potential therapeutic target for preventing and treating metastatic disease.

DOI: https://doi.org/10.1038/s41417-025-00977-7

Cell Death Dis. 2025 Oct 06. 16(1): 696

Overexpression of RUNX2 promotes breast cancer multi-organ metastasis through stabilizing c-Myc.

Tian-Hao Zhou, Hao Fu, Shuai Zhao, Wen-Jing Jiang, Sen Miao, Hao Tan, Rui Zhang, Qing-Shan Wang, Yu-Mei Feng.

Distant metastasis is the leading cause of mortality in breast cancer patients and remains a significant challenge in clinical practice. Although breast cancer metastasis exhibits organotropism, widespread dissemination and synchronous multi-organ metastasis frequently occur in advanced stages, or the early stages of patients suffering from aggressive tumors, even in patients with an undetectable primary tumor. However, the underlying mechanism is still far from being fully understood. Runt-related transcription factor 2 (RUNX2), a master osteogenic transcription factor, is commonly considered a driver of bone-specific metastasis in breast cancer. Surprisingly, we found here that overexpression of RUNX2 drives synchronous multi-organ metastases rather than bone-preferred metastasis in multiple mouse models of breast cancer, regardless of subtype. Mechanistically, RUNX2 physically interacts with c-Myc oncoprotein to prevent FBXW7-mediated ubiquitination and degradation of c-Myc and coordinately activates the transcription and expression of c-Myc target genes, which elicit early progression and spontaneous dissemination from primary tumor mass, rapid engraftment, and unrestrained outgrowth of cancer cells in distant organs. Thus, our findings uncover a novel mechanism of multi-organ metastasis and highlight RUNX2‒c-Myc regulatory axis as a prognostic indicator and a therapeutic target for predicting and managing multi-organ metastatic breast cancer.

DOI: https://doi.org/10.1038/s41419-025-08018-9

Cell Death Discov. 2025 Oct 06. 11(1): 430

Metabolic interplay between exogenous cystine and glutamine dependence in triple-negative breast cancer.

Ziqian Ge, Martina Wallace, Rory Turner, Maureen Yin, Mary F Rooney, Richard K Porter.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high recurrence rates and limited treatment options due to the absence of hormone receptors. Despite advancements in breast cancer research, effective therapies for TNBC remain inadequate, highlighting the need to elucidate subtype-specific metabolic vulnerabilities. TNBC cells exhibit a strong dependence on the exogenous amino acids cystine and glutamine, yet the interplay between these metabolic dependencies remains poorly understood. Here, we demonstrate that TNBC cells exhibit sensitivity to individual nutrient deprivation but can survive dual cystine and glutamine deprivation via distinct mechanisms. Exogenous glutamine primarily fuels glutamine anaplerosis, supporting TNBC cell proliferation. Notably, when exogenous glutamine is absent, restricted cystine uptake restores intracellular glutamate levels, fulfilling metabolic demands and sustaining TNBC cell growth. Under cystine deprivation, inhibition of glutaminolysis rescues TNBC cells by mitigating lipid peroxidation and reducing ROS production, whereas supplementation with the TCA cycle intermediates ɑ-ketoglutarate (ɑ-KG) and succinate induces profound cell death in both TNBC and luminal breast cancer cells under glutaminolysis blockade. Collectively, these findings highlight the metabolic interdependence of glutamine and cystine in TNBC, providing mechanistic insights into potential metabolic-targeted and dietary interventions for TNBC therapy.

DOI: https://doi.org/10.1038/s41420-025-02714-3

Sci Rep. 2025 Oct 08. 15(1): 35135

Contrasting roles of KMT2C and KMT2D in breast cancer.

Emily Tinsley, Philip Bredin, Sinead Toomey, Bryan T Hennessy, Simon J Furney.

KMT2C and KMT2D are paralogous lysine-methyltransferases that primarily monomethylate lysine residues at enhancer regions promoting an active transcriptional state. KMT2C and KMT2D are frequently mutated in multiple cancer types and in breast cancers mutations collectively occur at frequencies of 10-20%. However, the specificity and unique functions of the paralogues in breast cancer development are unclear. Using a combination of mutation, transcriptome, ChIP-seq, chromatin accessibility, and cell proliferation data from breast cancer patient and cell line samples we have investigated the roles of these proteins in tumour development. We identified a dependency of oestrogen receptor (ER) positive breast cancer cell lines on wildtype KMT2D. KMT2D ChIP-seq peaks show greater enrichment and interaction with ER and its binding partners FOXA1 and GATA3 compared to KMT2C in MCF-7 cells and uniquely bind enhancers of a set of genes enriched for oestrogen response pathways. Both KMT2C and KMT2D mutant luminal patient samples show significant downregulation of oestrogen response pathways compared to wildtype which, for KMT2C mutants, correlates with reduced chromatin accessibility around enhancers. Our results suggest that KMT2C and KMT2D have contrasting and subtype-specific roles in breast cancers and reveals KMT2D in particular as a potential target in ER + subtypes.

DOI: https://doi.org/10.1038/s41598-025-19027-1

Pharmacol Res. 2025 Oct 08. pii: S1043-6618(25)00403-7. [Epub ahead of print] 107978

PPM1G promotes chemoresistance in triple negative breast cancer by enhancing YAP signaling.

Weiling Huang, XuWei Chen, Haoming Wu, Chao Zhang, Wenjing Zhong, Xing Li, Ying Ouyang, Xiangfu Chen, Libing Song, Xi Wang, Kunpeng Hu, Zhenchong Xiong.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with the poorest prognosis. The frequent development of chemoresistance is a major therapeutic challenge, yet the underlying mechanisms remain unclear. Here, we found that PPM1G was upregulated in TNBC, and high PPM1G expression was significantly correlated with poor prognosis in TNBC patients who received chemotherapy. Overexpression of PPM1G enhanced, whereas its knockdown suppressed, cancer stem cell-like properties and chemoresistance of TNBC both in vitro and in vivo. Mechanistic investigations revealed that PPM1G interacted with NDR1 and dephosphorylated it at Thr444, which in turn reduced the YAP phosphorylation level at Ser127, finally inducing YAP nuclear translocation and enhancing its transcriptional activity. Moreover, treatment with a YAP inhibitor Verteporfin significantly attenuated the PPM1G-induced chemoresistance both in vitro and in vivo. Overall, our study elucidated a role of the PPM1G/NDR1/YAP axis in TNBC chemoresistance. We proposed that PPM1G may serve as a predictive biomarker for the treatment response of TNBC to YAP inhibitor.

Keywords: PPM1G; YAP; chemoresistance; triple-negative breast cancer

DOI: https://doi.org/10.1016/j.phrs.2025.107978