bims-merabr 2025-01-26 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–01–26
nine papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Targeting estrogen-regulated system xc- promotes ferroptosis and endocrine sensitivity of ER+ breast cancer.
LINC00626 drives tamoxifen resistance in breast cancer cells by interaction with UPF1.
FOXF2 expression triggered by endocrine therapy orchestrates therapeutic resistance through reorganization of chromatin architecture in breast cancer.
Extracellular matrix shapes cancer stem cell behavior in breast cancer: a mini review.
Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations.
Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer.
Zinc Finger SWIM-Type Containing 3 Reprograms Lipid Metabolism and Drives Breast Cancer Progression.
Effect of basic fibroblast growth factor on hypoxia-inducible factor (HIF)-1α expression (Exp) and HIF-1 transcription in breast Cancer cell through PI-3 K Akt signaling.
Targeting breast cancer stem cells in ER-positive breast cancer by repurposing the benzoporphyrin derivative verteporfin as a YAP/TAZ small molecule inhibitor.

Cell Death Dis. 2025 Jan 20. 16(1): 30

Targeting estrogen-regulated system xc- promotes ferroptosis and endocrine sensitivity of ER+ breast cancer.

Jiawei Cao, Tong Zhou, Tao Wu, Rixu Lin, Ju Huang, Dejin Shi, Jiawei Yu, Yinrui Ren, Changrui Qian, Licai He, Guang Wu, Zhixiong Dong, Shaofei Yuan, Haihua Gu.

Estrogen receptor positive (ER+) breast cancer accounts for approximately 70% of cases. Endocrine therapies targeting estrogen are the first line therapies for ER+ breast cancer. However, resistance to these therapies occurs in about half of patients, leading to decreased survival rates. Inducing ferroptosis is a promising therapeutic strategy for cancer treatment for refractory and malignant cancers including triple-negative breast cancer. Nevertheless, ER+ breast cancer is relatively resistant to ferroptosis inducers. Here, we uncovered that ERα suppressed ferroptosis in ER+ breast cancer. Silencing ERα triggered ferroptosis, which was attenuated by ferroptosis inhibitor Ferrostatin-1, and was enhanced by ferroptosis inducer Erastin. Mechanistically, ERα transcriptionally upregulated the expression of SLC7A11 and SLC3A2, two subunits of the system xc-, which is one key inhibitory regulator of ferroptosis. Overexpression of the exogenous SLC7A11 and SLC3A2 was able to mitigate ferroptosis induced by ERα inhibition. Moreover, SLC7A11 and SLC3A2 levels were elevated in endocrine-resistant breast cancer cells and tumors. Importantly, the system xc- inhibitor Sorafenib or Imidazole ketone erastin effectively inhibited the growth of tamoxifen-resistant breast cells in vitro and in vivo. In conclusion, our data reveal that targeting estrogen-regulated SLC7A11 and SLC3A2 enhances ferroptosis in ER+ breast cancer, offering a novel therapeutic option for patients with ER+ breast cancer, particularly those with endocrine resistance.

DOI: https://doi.org/10.1038/s41419-025-07354-0
Sci Rep. 2025 Jan 23. 15(1): 2997

LINC00626 drives tamoxifen resistance in breast cancer cells by interaction with UPF1.

Hui Yuan, Lianbang Zhou, Wei Hu, Min Yang.

  Although tamoxifen is commonly utilized as adjuvant therapy for Estrogen Receptor alpha (ERα)-positive breast cancer patients, approximately 30-50% of individuals treated with tamoxifen experience relapse. Therefore, it is essential to investigate additional factors besides ERα that influence the estrogen response. In this study, cross-analysis of databases were performed, and the results revealed a significant association between LINC00626 and ERα signaling as well as increased expression levels of this gene in tamoxifen-resistant cells. LINC00626 is a novel ERα-regulated long non-coding RNA (lncRNA) that has not yet been examined for its potential contribution to endocrine therapy resistance. This study revealed that the upregulation of LINC00626 in breast cancer was associated with poor overall survival in patients. Additionally, ERα signaling was found to transcriptionally regulate LINC00626 expression, thereby promoting cancer progression and enhancing resistance to tamoxifen in breast cancer cells via the regulation of UPF1 expression. Depletion of LINC00626 restored sensitivity to tamoxifen by activating the PERK-ATF4-CHOP signaling pathway via UPF1. These findings support the role of LINC00626 as a potential therapeutic target for combating tamoxifen resistance.

Keywords:  Apoptosis; Estrogen; LINC00626; Tamoxifen resistance; UPF1

DOI:  https://doi.org/10.1038/s41598-025-86287-2
Cancer Lett. 2025 Jan 17. pii: S0304-3835(25)00027-8. [Epub ahead of print] 217463

FOXF2 expression triggered by endocrine therapy orchestrates therapeutic resistance through reorganization of chromatin architecture in breast cancer.

Rui Zhang, Wen-Jing Jiang, Shuai Zhao, Li-Juan Kang, Qing-Shan Wang, Yu-Mei Feng.

  Patients with estrogen receptor-positive (ER+) breast cancer require long-term endocrine therapy. However, endocrine resistance remains a critical issue to be addressed. Herein, we show that ERα repressed FOXF2 transcription in ER+ breast cancer through H3K27me3 modification, therefore endocrine therapy triggered FOXF2 transcription via loss of H3K27me3. FOXF2 transactivation orchestrated endocrine resistance and bone metastasis. Mechanistically, FOXF2 globally activated enhancers of genes involved in epithelial-mesenchymal transition/epithelial-osteogenic transition, as well as super-enhancers of NCOA3 (a coactivator of FOXF2) and SP1 (an upstream transactivator of FOXF2) by recruiting the SWI/SNF complex that mediates the reorganization of chromatin architecture. Forthermore, FOXF2 systematically modulates the reorganization of chromatin architecture and gene expression by recruiting SMARCC1. Therefore, FOXF2 acts as a pioneer factor to orchestrate endocrine resistance through the reorganization of chromatin architecture. Additionally, FOXF2 expression levels in the tumors of ER+ breast cancer predicted response to endocrine therapeutic drugs and outcome of patients. Targeting BRD4, an essential transcriptional coactivator of FOXF2, significantly inhibited FOXF2-orchestrated endocrine-resistance and bone metastasis. Our findings uncover a mechanism underlying endocrine resistance and provide a promising strategy for managing endocrine-resistant breast cancer.

Keywords:  Endocrine-resistant breast cancer; Enhancer; FOXF2; SWI/SNF complex; Super-enhancer

DOI:  https://doi.org/10.1016/j.canlet.2025.217463
Front Immunol. 2024 ;15 1503021

Extracellular matrix shapes cancer stem cell behavior in breast cancer: a mini review.

Lei Li, Yidan Tang, Ling Qiu, Zhengrui Li, Ruo Wang.

  Today, cancer has become one of the leading global tragedies. It occurs when a small number of cells in the body mutate, causing some of them to evade the body's immune system and proliferate uncontrollably. Even more irritating is the fact that patients with cancers frequently relapse after conventional chemotherapy and radiotherapy, leading to additional suffering. Scientists thereby presume that cancer stem cells (CSCs) are the underlying cause of metastasis and recurrence. In recent years, it was shown that not only can chemotherapy and radiotherapy underperform in the treatment of breast cancer, but they can also increase the number of breast cancer stem cells (BCSCs) that transform regular breast cancer cells into their own population. Such data somewhat support the aforementioned hypothesis. Meanwhile, our understanding of the extracellular matrix (ECM) has changed considerably over the last decade. A lot of studies have bit by bit complemented human knowledge regarding how the ECM greatly shapes the behaviors of BCSCs. In this review, we highlighted the influence on BCSCs exerted by different critical components and biochemical properties of ECM.

Keywords:  BCSCs; ECM; breast cancer; cancer stem cells; extracellular matrix

DOI:  https://doi.org/10.3389/fimmu.2024.1503021
Cancer Res. 2025 Jan 22.

Comparison of Lean, Obese, and Weight Loss Models Reveals TREM2 Deficiency Attenuates Breast Cancer Growth Uniquely in Lean Mice and Alters Clonal T Cell Populations.

Elysa W Pierro, Matthew A Cottam, Hanbing An, Brian D Lehmann, Jennifer A Pietenpol, Kathryn E Wellen, Liza Makowski, Jeffrey C Rathmell, Barbara Fingleton, Alyssa H Hasty.

Obesity is an established risk factor for breast cancer development and poor prognosis. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression, and TREM2, a transmembrane receptor expressed on macrophages in adipose tissue and tumors, is an emerging therapeutic target for cancer. A better understanding of the mechanisms for the obesity-breast cancer association and the potential benefits of weight loss could help inform treatment strategies. Here, we utilized lean, obese, and weight loss mouse models to examine the impacts of TREM2 deficiency (Trem2+/+ and Trem2-/-) on postmenopausal breast cancer depending on weight history conditions. Trem2 deficiency constrained tumor growth in lean, but not obese or weight loss, mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed differences in the immune landscapes across the different models. Tumors of lean Trem2-/- mice exhibited a shift in clonal CD8+ T cells from an exhausted to an effector memory state, accompanied increased clonality of CD4+ Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adj of the same mouse. Finally, anti-PD-1 therapy restricted tumor growth in lean and weight loss, but not obese, mice. These findings indicate that weight history could impact the efficacy of TREM2 inhibition in postmenopausal breast cancer. The reported immunological interactions between tumors and the surrounding adipose tissue highlight significant differences under obese and weight loss conditions.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3511
Cell J. 2025 Jan 08. pii: 715803. [Epub ahead of print]26(9): 543-558

Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer.

Babak Jahangiri, Zahra-Soheila Soheili, Elahe Asadollahi, Mehdi Shamsara, Vahid Shariati, Alireza Zomorodipour.

   OBJECTIVE: The aim of this study was to understand the interactions between tumor-associated mesenchymal stem cells (TA-MSCs) and triple-negative breast cancer (TNBC) cells, which appear to be necessary for developing effective therapies.
MATERIALS AND METHODS: In this experimental study, MDA-MB-231 and 4T1 TNBC cells were co-cultured with bone marrow-derived MSCs, and TA-MSCs conditioned media (CM) were collected. TA-MSC CM-treated TNBC cells were subjected to migration and invasion assays. Epithelial-mesenchymal transition (EMT) marker expression was quantified by real-time polymerase chain reaction (RT-PCR). Cell proliferation was measured using trypan blue exclusion technique, while cell cycle distribution and apoptosis were assessed by flow cytometry. The effects of TA-MSCs on tumor volume, survival rate, and lung metastasis were evaluated by subcutaneous co-injection of MSCs with 4T1 cells in the right flanks of BALB/c mice (n=5 per group). Intratumoral interleukin-12 (IL-12) immunotherapy was performed using lentiviral particles as a rescue experiment. The TA-MSCs RNA-seq dataset (PRJEB27694) was analyzed to detect elevated metastasis-associated oncogenes, downloaded from the European Nucleotide Archive database. For validation of the RNA-seq data analysis, the expression levels of candidate oncogenes were evaluated in TA-MSCs, TNBC cells, and tumor tissue using RT-PCR.
RESULTS: TA-MSCs enhanced migration, invasion, and EMT of TNBC cells in vitro without affecting cell proliferation or apoptosis. In vivo, TA-MSCs increased tumor growth and lung metastasis, while decreasing survival rates. IL-12 therapy elevated serum IL-12 and interferon-gamma (IFN-γ) expression, suppressed tumor volume and lung metastasis, and improved overall survival in the TA-MSC group. RNA-seq data analysis identified upregulated oncogenes in TA-MSCs, among which MMP3, CXCL2, CXCL5, and ICAM1 were selected as the most relevant to metastasis. These genes showed increased expression in TA-MSCs, TNBC cells, and tumor tissues.
CONCLUSION: The findings of the present study revealed a complex interplay between TA-MSCs and TNBC cells that affects tumor growth and metastasis. Preclinical results indicate that intratumoral IL-12 immunotherapy shows promise in overcoming TA-MSC-promoted tumor growth and metastasis.

Keywords:  Immunotherapy; Interleukin-12; Metastasis; RNA-Seq; Triple-Negative Breast Cancer

DOI:  https://doi.org/10.22074/cellj.2024.2036513.1634
Discov Med. 2025 Jan;37(192): 152-165

Zinc Finger SWIM-Type Containing 3 Reprograms Lipid Metabolism and Drives Breast Cancer Progression.

Xiao Ma, Ancai Wang, Yu Wang, Jintao Ma, Yunchong Liu, Yu Mei.

   BACKGROUND: Zinc finger proteins (ZNFs) have been proved to play important roles in driving the progression of breast cancer (BC), one of the most common cancers among women. This study aimed to investigate the involvement of zinc-finger SWIM domain-containing protein 3 (ZSWIM3) in promoting BC cell progression by regulating lipid metabolism.
METHODS: Differential expression of ZSWIM3 in BC was confirmed by comparing its expression in normal human mammary epithelial cells and BC cells. MCF7 cells, a BC cell line, were subjected to ZSWIM3 knockdown/overexpression experiments. The lipid contents in MCF7 cells were measured by assay kits and immunofluorescence test. The lipogenic enzymes in the cells were detected by enzyme-linked immunosorbent assay (ELISA). The cells were also subjected to further transfection experiments to manipulate the expression of sterol regulatory element-binding transcription factor 1 (SREBF1)/SREBF2 in ZSWIM3-regulated MCF7 cells to verify whether the ZSWIM3 targets SREBF1/SREBF2. Subsequently, the lipid contents in the transfected cells were determined, and the cell viability, proliferation and metastasis were measured.
RESULTS: ZSWIM3 was overexpressed in BC cells. ZSWIM3 knockdown/overexpression led to a significant decrease/increase of the lipid contents including triglyceride, free fatty acid, cholesterol, phospholipid and neutral lipid, and lipogenic enzymes (p < 0.01). The ZSWIM3 knockdown decreased the expression of SREBF1 and SREBF2 (p < 0.01). Our findings showed that lipid content reduction induced by ZSWIM3 knockdown was reversed by SREBF1/SREBF2 overexpression. MCF7 cell viability, proliferation and metastasis, which were all suppressed by ZSWIM3 knockdown (p < 0.001), were reversible through SREBF1/SREBF2 overexpression (p < 0.001). On the other hand, the ZSWIM3 overexpression increased SREBF1 and SREBF2 expression (p < 0.001). Lipid content elevation, as well as increased MCF7 cell viability, proliferation and metastasis, which were induced by ZSWIM3 overexpression, could be counteracted by SREBF1/SREBF2 downregulation (p < 0.001).
CONCLUSION: ZSWIM3 promotes BC progression by enhancing lipid synthesis. This study reveals the malevolent effect of ZSWIM3 on BC, underpinned by the reprogramming of lipid metabolism, providing insights into potential therapeutic targets for BC treatments.

Keywords:  SREBF1; SREBF2; ZSWIM3; breast cancer; lipid metabolism

DOI:  https://doi.org/10.24976/Discov.Med.202537192.13
Cytokine. 2025 Jan 17. pii: S1043-4666(25)00006-7. [Epub ahead of print]187 156859

Effect of basic fibroblast growth factor on hypoxia-inducible factor (HIF)-1α expression (Exp) and HIF-1 transcription in breast Cancer cell through PI-3 K Akt signaling.

Chengcai Zhang, Jinxia Yu, Shuaifeng Li.

   OBJECTIVE: To investigate the effect of basic fibroblast growth factor (bFGF) on hypoxia-inducible factor (HIF)-1α expression (Exp) and HIF-1 transcription in breast cancer (BC) cells.
METHODS: Human BC cell line T47D was utilized as the research object. Western blot and dual-luciferase system were utilized to detect HIF-1α Exp induced by bFGF in BC cells under hypoxia and normal oxygen conditions, as well as the Exp of phosphorylated ERK1/2, Akt, and p38 proteins, HIF-1α Exp induced by bFGF under kinase inhibitors' action, and HIF-1 transcription, thereby summarizing the impact of bFGF on BC cells and its association with PI-3 K Akt signaling pathway (SPW).
RESULTS: The maximum Exp fold was 4.9 when the induced dose of bFGF was 10 ng/mL under hypoxia, and the maximum Exp fold of HIF-1α was 7 at 3 h (180 min). Under normal oxygen condition, cycloheximide inhibited HIF-1α protein Exp, and the reduction was up to 50 % within 30 min. Various doses of kinase inhibitor SU5402 inhibited HIF-1α protein Exp, and the inhibition rate was 100 %. The kinase inhibitors SU5402, PD98059, and LY294002 all had marked effects on bFGF-induced HIF-1 transcription.
CONCLUSION: Both MEK1/ERK and PI-3 K/Akt SPW play crucial roles in bFGF-mediated HIF-1 activation. BFGF had a notable activation of HIF-1. PI-3 K/Akt and MEK1/ERK SPW worked together to regulate this process by various mechanisms.

Keywords:  BC; Basic fibroblast growth factor; HIF-1; HIF-1α

DOI:  https://doi.org/10.1016/j.cyto.2025.156859
Mol Biol Rep. 2025 Jan 24. 52(1): 154

Targeting breast cancer stem cells in ER-positive breast cancer by repurposing the benzoporphyrin derivative verteporfin as a YAP/TAZ small molecule inhibitor.

Priyanka Dey Talukdar, Himansu Roy, Urmi Chatterji.

   BACKGROUND: Current treatment strategies for hormone-dependent breast cancers, including adjuvant endocrine therapy, often fail due to persistence of breast cancer stem cells (brCSCs), which are significant contributors to tumor recurrence and treatment resistance. Therefore, gaining deeper insights into the molecular regulators driving breast cancer aggressiveness is important. Moreover, given the complexities and expenses involved in developing new pharmacological agents, the strategic repurposing of existing FDA-approved drugs to target these key molecular pathways presents a compelling approach for identifying novel therapeutic interventions aimed at mitigating tumor refractoriness.
METHODS: The study employs survival analysis from TCGA database, protein expression analyses alongside aldefluor assays, sphere formation efficiency tests to evaluate cellular stemness, and DCFDA analysis combined with antioxidant enzyme assays to investigate redox imbalance in brCSCs. These analyses were conducted following the genetic deletion of YAP/TAZ and pharmacological treatment with verteporfin.
RESULTS: The study demonstrated that transcriptional co-activators YAP/TAZ are significantly upregulated in chemotreated ER+ patient breast tumors and MCF-7 mammospheres, where it was found to interact with the transcription factor SOX2 within the nuclear compartment. Genetic ablation and pharmacological inhibition of YAP/TAZ markedly impaired stemness properties and disrupted redox homeostasis in the mammospheres. Additionally, treatment with verteporfin led to a substantial reduction in the frequency and viability of brCSCs, suggesting their effective eradication.
CONCLUSION: This study highlights the potential of repurposing verteporfin, an FDA-approved drug originally formulated for age-related macular degeneration, as a therapeutic agent for targeting YAP/TAZ-mediated stemness and redox balance in brCSCs, thereby reducing their viability in ER-positive breast cancers.

Keywords:  Breast cancer stem cells; Drug repurposing; ER-positive breast cancer; Verteporfin; YAP/TAZ

DOI:  https://doi.org/10.1007/s11033-025-10264-1