bims-merabr 2026-06-07 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–06–07
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

BRD4 PROTAC degrader enhances fulvestrant sensitivity in ER+ breast cancer via super-enhancer associated GREB1.
Effects of SOX10 on the proliferative, invasive, migratory, and epithelial-mesenchymal transition abilities of triple-negative breast cancer cells.
Ferroptosis in breast cancer: From adipocyte-immune-iron regulation to therapeutic application.
Cancer-associated adipomes promote invadopodia formation and enhance metastatic potential in triple-negative breast cancer.
Shaping breast cancer progression in obesity: Insights from advanced models and omics tools.
ZNF468 Exhibits Oncogenic Activity by Regulating Unexplored ZNF707 in Breast Cancer.
Hydrostatic pressure activates HIF-1α via β-catenin to promote stemness in breast cancer cells.
NF1 loss in estrogen receptor-positive breast cancer induces osteoclast formation and immunosuppression to promote bone metastasis.

Front Oncol. 2026 ;16 1828900

BRD4 PROTAC degrader enhances fulvestrant sensitivity in ER+ breast cancer via super-enhancer associated GREB1.

Xiulei Zhang, Peiming Zheng, Zhengyi Liu, Qian Zhang, Wenjing Duan, Tingting Zhang, Xiaozhuan Liu.

   Background: Breast cancer has the highest incidence and mortality among all cancers affecting women. Fulvestrant resistance remains a major clinical challenge that limits the efficacy of endocrine therapies. BRD4, a transcriptional regulator that recognizes acetylated histones, is implicated in the pathogenesis and progression of various tumors, including breast cancer. However, its role in fulvestrant sensitivity and the therapeutic potential of targeted BRD4 degradation require further investigation.
Methods: We assessed BRD4 transcriptional activity in breast cancer and its functional role in tumor progression and endocrine sensitivity. The antitumor effect of a PROTAC-targeted BRD4 degrader, alone or in combination with fulvestrant, was evaluated in breast cancer cells. Integrated analysis of BRD4 and estrogen receptor (ER) chromatin immunoprecipitation sequencing (ChIP-seq) datasets was performed to identify co-occupied genomic regions and downstream targets. GREB1 was identified as a key effector and further validated as a super-enhancer-associated gene. The working mechanism of BRD4 PROTAC and fulvestrant was investigated through GREB1 signaling disruption.
Results: The occupancy of BRD4 at promoter regions was found to be increased in breast cancer, and its high expression indicated poor clinical outcome among ER+ breast cancer patients with endocrine therapy. A PROTAC-targeted BRD4 degrader significantly enhanced the antitumor efficacy of fulvestrant in breast cancer cells. Integrated ChIP-seq analysis revealed substantial co-occupancy of BRD4 and ER on shared pathways and identified GREB1 as a critical downstream effector regulated by a BRD4-associated super-enhancer. Mechanistically, the BRD4 PROTAC enhances fulvestrant sensitivity by down-regulation of GREB1 expression.
Conclusion: Targeting BRD4 with PROTAC degraders represents a promising therapeutic strategy in breast cancer by suppressing GREB1 expression and enhancing the efficacy of fulvestrant.

Keywords:  BRD4; GREB1; PROTAC; breast cancer; fulvestrant sensitivity

DOI:  https://doi.org/10.3389/fonc.2026.1828900
Front Oncol. 2026 ;16 1769833

Effects of SOX10 on the proliferative, invasive, migratory, and epithelial-mesenchymal transition abilities of triple-negative breast cancer cells.

Shuai Wang, Linfang Jin.

   Introduction: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited targeted therapeutic options. Sry-related HMG-box gene 10 (SOX10) has been implicated in tumor progression in various malignancies, but its functional role and underlying mechanism in TNBC remain unclear. This study aimed to investigate the effect of SOX10 on TNBC cell proliferation, metastasis, and epithelial-mesenchymal transition (EMT), and to explore its association with the Wnt/β-catenin signaling pathway.
Methods: HCC1937 cells (high endogenous SOX10 expression) and MDA-MB-453 cells (low endogenous SOX10 expression) were used for SOX10 knockdown and overexpression experiments. Wnt pathway activators and inhibitors were applied in rescue experiments to validate the mechanistic link. Cell proliferation was assessed by CCK-8 assay; migration and invasion were evaluated by scratch wound and Transwell assays, respectively. The expression levels of EMT markers and Wnt/β-catenin pathway-related proteins were quantified by Western blot analysis.
Results: SOX10 overexpression significantly promoted proliferation, migration, and invasion in both TNBC cell lines, while SOX10 knockdown markedly inhibited these abilities (all P<0.05). SOX10 upregulated the expression of mesenchymal markers (Vimentin, N-cadherin) and Wnt/β-catenin pathway components (WNT1, nuclear β-catenin, C-myc, Cyclin D1), and downregulated the epithelial marker E-cadherin (all P<0.05). Rescue experiments confirmed that Wnt pathway activation reversed the EMT suppression induced by SOX10 knockdown, while Wnt pathway inhibition attenuated the EMT promotion caused by SOX10 overexpression (all P<0.05).
Discussion: SOX10 promotes malignant biological behaviors in TNBC cells by activating the Wnt/β-catenin signaling pathway and inducing EMT. These findings suggest that the SOX10-Wnt/β-catenin axis may serve as a potential therapeutic target for TNBC, warranting further mechanistic and translational investigation.

Keywords:  SOX10; Wnt/β-catenin pathway; cellular biological behavior; epithelial-mesenchymal transition; triple negative breast cancer

DOI:  https://doi.org/10.3389/fonc.2026.1769833
Clin Transl Med. 2026 Jun;16(6): e70707

Ferroptosis in breast cancer: From adipocyte-immune-iron regulation to therapeutic application.

Juan Sun, Yang Qu, Ru Yao, Yidong Zhou.

   BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential therapeutic vulnerability in breast cancer. However, increasing evidence indicates that ferroptosis sensitivity is not solely determined by tumour-intrinsic factors, but is dynamically regulated by the tumour microenvironment (TME), particularly through interactions among adipocytes, immune cells and iron metabolism.
MAIN BODY: Recent studies provide mechanistic evidence for this context dependence. Adipocyte-derived monounsaturated fatty acids such as oleic acid suppress lipid peroxidation and increase resistance to ferroptosis induction in triple-negative breast cancer, whereas ACSL4-driven polyunsaturated phospholipid remodelling enhances ferroptosis susceptibility. In parallel, CD8+ T-cell-derived interferon-γ promotes ferroptosis by suppressing SLC7A11-mediated cystine uptake, while tumour-associated macrophages buffer oxidative stress through iron sequestration and glutathione-dependent antioxidant programs. These opposing forces indicate that ferroptosis is governed by a coordinated adipocyte-immune-iron regulatory network rather than a single pathway. Unlike previous reviews focused mainly on tumour-intrinsic mechanisms or general TME effects, this review integrates adipocyte-derived lipid metabolism, immune-mediated redox regulation, iron handling and spatial heterogeneity into a unified 'ferroptosis ecosystem' framework. Based on this concept, we propose eco-ferrotherapy, a translational strategy aimed at simultaneously targeting tumour-intrinsic pathways and microenvironmental buffering systems. This framework may support subtype-specific therapeutic prioritisation, biomarker-guided patient stratification and rational combination strategies involving immunotherapy and nanomedicine.
CONCLUSION: Ferroptosis in breast cancer should be understood as an ecosystem-level vulnerability shaped by metabolic, immune and spatial factors. Defining and therapeutically targeting this ferroptosis ecosystem provides a conceptual and translational roadmap for improving precision treatment strategies.

Keywords:  adipocytes; breast cancer; ferroptosis; immune cells; iron metabolism; precision medicine; tumour microenvironment

DOI:  https://doi.org/10.1002/ctm2.70707
NPJ Breast Cancer. 2026 Jun 03.

Cancer-associated adipomes promote invadopodia formation and enhance metastatic potential in triple-negative breast cancer.

Hariprasad Thangavel, Dhanya Dhanyalayam, Kezia Lizardo, Shivani Bansal, Junfeng Ma, Robert Glazer, Jyothi Nagajyothi.

Triple-Negative Breast Cancer (TNBC), which accounts for 15-20% of all breast cancer cases, remains one of the most aggressive and therapeutically challenging subtypes due to its lack of hormone receptors and HER2 expression, leaving chemotherapy as the primary treatment option. TNBC is characterized by early relapses and visceral metastasis, underscoring the urgent need to elucidate the mechanisms driving metastasis. The metastatic cascade begins with cancer cell invasion of the surrounding stroma, a process mediated by actin-rich protrusions called invadopodia that degrade the extracellular matrix (ECM). While the molecular machinery of invadopodia is well characterized, the upstream tumor microenvironment (TME) signals that regulate their formation remain poorly understood. In breast cancer, the TME is predominantly composed of mammary adipose tissue, where adipocytes undergo reprogramming into cancer-associated adipocytes (CAAs) that release extracellular vesicles, termed 'adipomes'. These adipomes serve as intercellular messengers, transferring bioactive molecules that can alter tumor cell behavior. Using a novel purification method, large (L)-adipomes were isolated from the plasma of TNBC subjects as well as from tumor-associated mammary fat (TAMF) using a murine TNBC model (EO771-C57BL/6) to investigate their role in invasion. Circulating L-adipomes from metastatic TNBC subjects induced epithelial-to-mesenchymal transition (EMT) and stemness signaling and promoted invadopodia formation in human non-tumorigenic breast epithelial cells, while TAMF-derived L-adipomes from metastatic-stage mice were enriched in phospholipids and promoted transcriptional and functional reprogramming in murine TNBC cells. Integrated transcriptomic and proteomic analyses revealed that adipomes activate stress-responsive MAPK signaling and upregulate proteins involved in actin cytoskeletal remodeling, mitochondrial metabolism, and translational machinery, pathways known to support invadopodia formation and extracellular matrix (ECM) degradation. Together, these findings establish adipocyte-derived adipomes as potent regulators of TNBC invasion and metastasis and reveal a previously unrecognized tumor-adipocyte signaling axis that may present new opportunities for therapeutic targeting.

DOI: https://doi.org/10.1038/s41523-026-00985-2
Biochim Biophys Acta Rev Cancer. 2026 Jun 03. pii: S0304-419X(26)00097-1. [Epub ahead of print]1881(4): 189625

Shaping breast cancer progression in obesity: Insights from advanced models and omics tools.

Rosalia Emma, Valentina Sergi, Domenica Scordamaglia, Paolo Scollo, Robert B Clarke, Roberta Malaguarnera, Ernestina Marianna De Francesco.

  Obesity is a negative prognostic factor in BC, a heterogeneous and complex disease representing the leading cause of mortality from female cancer. Within the breast tumour microenvironment (TME), adipocytes, fibroblasts, immune cells and the extracellular matrix are aberrantly activated in obesity, leading to inflammatory responses, together with hormonal and metabolic changes, and activation of oncogenic pathways that facilitate disease progression. To fully grasp the metabolic complexity and heterogeneity of obese BC patients, proper experimental models, able to mimic the aberrant interactions occurring within the obese breast TME, are required. Herein, we first present the most recent findings on the players involved in the remodelling of the breast TME during obesity. Next, we highlight the main advanced preclinical models used to investigate the interaction between obesity and BC, including immunocompetent and immunodeficient in vivo systems, as well as advanced 3D in vitro and ex vivo models. We focus on the integration of these models with advanced omics techniques, such as transcriptomics, proteomics and metabolomics, toward a more systematic and dynamic view of the obesity-BC link. Finally, we discuss the current limitations of available models and the future prospects to advance knowledge in the field.

Keywords:  Advanced 3D models; Animal models; Breast cancer; Metabolomic; Obesity; Omics; Preclinical models; Proteomic; Transcriptomic; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189625
J Gene Med. 2026 Jun;28(6): e70099

ZNF468 Exhibits Oncogenic Activity by Regulating Unexplored ZNF707 in Breast Cancer.

Manas K Mahapatra, Shivani Bansal, Sweta H Makwana, Sudip Ghosh, Alo Nag, Sandeep K Shrivastava, Rekha Maheshwari, Chandi C Mandal.

   BACKGROUND: Dysregulation of transcription factors potentiates cancer cell proliferation, stemness, cellular plasticity, metastasis, and therapy resistance and also links with diagnosis/prognosis of the diseases. Thus, investigation of uncharacterized transcription factors is a prime aim for designing novel therapeutics. Large family C2H2 type zinc finger proteins (ZNFs) often bind to nucleic acids and also act as transcription factors. However, unregulated expression of these ZNFs was found to cause diverse pathological conditions including cancer.
METHODS: Cancer database and specific GEO analysis were used to screen unexplored ZNFs. Subsequent knockdown and overexpression studies of selected ZNFs were conducted to examine their oncogenicity in breast cancer cells. Database analysis, ChIP, and knockdown study identified target genes. Overexpression and rescue experiments identified the oncogenic potential of target genes. The chemo-sensitivity of the target gene was determined. RT-qPCR analysis of breast cancer tissues confirms the oncogenic potential of the ZNFs.
RESULTS: A systematic cancer database analysis using differential gene expressions (fold change between tumor and control tissue) and patient survivability (hazard ratio) found three unexplored ZNFs in breast cancer. Subsequent GEO database analysis determined ZNF468 for further experimentation. Knockdown of the gene ZNF468 showed inhibition of various oncogenic potentials including cell proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) and oncogenic markers (e.g., Bcl-2, Vimentin, and Zeb2) in both MCF-7 and MDA-MB-231 breast cancer cells. Database analysis found consensus DNA binding site of the ZNF468 in unexplored gene ZNF707, further confirmed by ChIP assay and knockdown of ZNF468. Subsequently, overexpression of ZNF707 gene upregulated cell proliferation, migration, invasion, and oncogenic markers in both MCF-7 and MDA-MB-231 cells. ZNF468 knockdown also inhibited the expression of various cholesterol regulatory genes. Furthermore, the oncogenic activity of ZNF468 in MCF-7 cells was revived by the overexpression of ZNF707. Overexpression of ZNF707 reduced the effectiveness of doxorubicin treatment. Finally, compared to benign, expression of both ZNF468 and ZNF707 was higher in malignant breast cancer patient tissue.
CONCLUSIONS: These findings for the first time documented the oncogenic potential of ZNF707 in breast cancer. Additionally, ZNF468 promotes its oncogenic activity by regulating ZNF707 expression. Thus, these two ZNFs may be further explored to design promising therapy for breast cancer treatment.

Keywords:  ZNF707 and ZNF468; breast cancer; differential expression and survival analysis; knockdown and overexpression study; zinc finger proteins (ZNFs)

DOI:  https://doi.org/10.1002/jgm.70099
FEBS Open Bio. 2026 Jun 01.

Hydrostatic pressure activates HIF-1α via β-catenin to promote stemness in breast cancer cells.

Da Zhai, Yong Xu, Jingjing Ma, Ratchanee Duangrat, Chen Yan, Jingyan Liang, Hua Wei, Bin Jiang, Tao-Sheng Li.

  Tumor microenvironment plays a pivotal role in regulating the biological properties of cancer cells. Interstitial fluid hydrostatic pressure (HP) generally increases in malignant solid tumors. While our recent work has demonstrated that elevated HP stabilizes HIF-1α expression in cancer cells, here we further investigate whether elevated HP promotes cancer cells to acquire stemness features. Our results showed that exposure to 50 mmHg HP for 48 h did not significantly change the survival or morphology of human breast cancer cells. However, 50 mmHg HP stimulation significantly increased aldehyde dehydrogenase (ALDH) activity and upregulated HIF-1α and stemness markers (CD44 and SSEA-1) in MCF-7 and BT-474 but not in MDA-MB-453 breast cancer cell lines. Correspondingly, β-catenin was significantly enhanced in MCF-7 and BT-474 breast cancer cell lines under 50 mmHg HP stimulation and was negatively expressed in MDA-MB-453 breast cancer cells. Hypoxia (1% O2) exposure for 48 h also significantly enhanced the expression of β-catenin only in MCF-7 cells and BT-474 breast cancer cell lines, but increased HIF-1α expression and ALDH activity in all breast cancer cell lines tested, including the β-catenin-deficient MDA-MB-453 cells. Therefore, we conclude that elevated HP in malignant tumors may facilitate the acquisition of 'stemness' characteristics of cancer cells by enhancing HIF-1α expression via β-catenin.

Keywords:  ALDH; HIF‐1α; hydrostatic pressure; stemness; β‐catenin

DOI:  https://doi.org/10.1002/2211-5463.70267
Cancer Lett. 2026 May 29. pii: S0304-3835(26)00399-X. [Epub ahead of print]655 218636

NF1 loss in estrogen receptor-positive breast cancer induces osteoclast formation and immunosuppression to promote bone metastasis.

Zifan Zhao, Ze-Yi Zheng, Jonathan T Lei, Matthew J Baik, Yi-Hsuan Wu, Lauren K Somes, Andres F Mosquera Paternina, Omar A Harb, Owen A Chang, Fengshuo Liu, Matthew V Holt, Junkai Wang, Igor Bado, Hai Wang, George Miles, Zbigniew Gugala, Meenakshi Anurag, Ahmed Elkhanany, Yi Li, Valentina Hoyos, Xiang H-F Zhang, Eric C Chang.

  Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. Furthermore, after intra-iliac injection, NF1-depleted cells generated significantly greater tumor burden in bone. Transcriptomic profiling revealed enrichment of bone-related gene signatures in NF1-depleted ER+ breast cancer cells, which more potently induced osteoclast differentiation and bone loss in co-culture systems. In parallel, low NF1 expression correlated with repressed T cell functional states in primary breast tumors and bone metastases. Consistent with these clinical observations, NF1-depleted ER+ breast cancer cells more effectively inhibited proliferation, interferon-γ secretion, and cytotoxicity of human primary CD8+ T cells. Collectively, these findings identify NF1 inactivation as a key driver of bone metastasis in a substantial subset of ER+ breast cancers. By amplifying the osteolytic "vicious cycle" and promoting immune evasion, NF1 loss remodels the microenvironment to favor tumor expansion. These results further suggest that NF1 loss functionally links therapy resistance with increased skeletal metastatic potential.

Keywords:  And osteoporosis; Cytotoxicity; Estrogen response; Osteogenesis; RAS; Steroid hormone nuclear receptor; T cell exhaustion; T cell infiltration; Transcriptional co-repressor

DOI:  https://doi.org/10.1016/j.canlet.2026.218636