bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–06–15
thirteen papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. FGFR1 overexpression promotes resistance to PI3K inhibitor alpelisib in luminal breast cancer cells through receptor tyrosine kinase signaling-mediated activation of the estrogen receptor.
  2. STEAP3 promotes triple-negative breast cancer growth through the FGFR1-mediated activation of PI3K/AKT/mTOR signaling.
  3. Targeting the leptin receptor promotes MDA-MB-231 cells' metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue.
  4. Unveiling the impact of lipid metabolism on triple-negative breast cancer growth and treatment options.
  5. New Insights Into Adipokines and the Tumor Microenvironment in Breast Cancer.
  6. LMO2 regulates epithelial-mesenchymal plasticity of mammary epithelial cells.
  7. HIF-1α-Mediated Disruption of Cellular Junctions: The Impact of Hypoxia on the Tumor Microenvironment and Invasion.
  8. Oxygen deprivation in breast cancer: mechanisms, pathways, and implications.
  9. The Mechanical Properties of Breast Cancer Cells and Their Surrounding Microenvironment.
  10. PTPN2 inhibits TG-induced ERS-initiated TNBC apoptosis through the mitochondrial pathway.
  11. Hyperglycemic state and fluid shear stress affect metastatic breast cancer cell migration via focal adhesion kinase.
  12. Astrocyte reprogramming drives tumor progression and chemotherapy resistance in agent-based models of breast cancer brain metastases.
  13. Lactate Is a Major Promotor of Breast Cancer Cell Aggressiveness.
  1. Cancer Drug Resist. 2025 ;8 24
    FGFR1 overexpression promotes resistance to PI3K inhibitor alpelisib in luminal breast cancer cells through receptor tyrosine kinase signaling-mediated activation of the estrogen receptor.
    Yujie Shi, Lexia Chen, Qiong Cheng, Peijia Niu, Yahan Weng, Xiaohe Yang.
      Aim: Resistance to PI3K inhibitor alpelisib is an emerging challenge in breast cancer treatment. FGFR1 is frequently amplified in breast cancer. We investigated FGFR1 overexpression-mediated alpelisib resistance and its mechanism. Methods: CCK-8, colony formation, and cell cycle assays assessed FGFR1 overexpression-induced alpelisib resistance in MCF-7 and T47D cells. FGFR1 siRNA knockdown validated FGFR1's role. Akt, Erk, and ER signaling were analyzed by Western blot. Synergistic effects of alpelisib with AZD4547 and fulvestrant were evaluated using the combination index. Results: FGFR1 overexpression conferred alpelisib resistance in MCF-7 and T47D cells, evidenced by increased viability, colony formation, and S-phase accumulation post alpelisib treatment. Knockdown of FGFR1 reverse alpelisib resistance in FGFR1 overexpressing MCF-7 and T47D cells. Resistance correlated with sustained activation of Akt and Erk1/2 pathways (p-Akt, p-Erk1/2, p-S6K, p-Rb) and attenuated suppression of ERα phosphorylation (S118/S167), highlighting RTK-ER crosstalk. Combining alpelisib with AZD4547 synergistically inhibited growth and suppressed both RTK signaling and ERα phosphorylation. While alpelisib-fulvestrant was effective, adding AZD4547 further enhanced inhibition, supporting triple therapy to overcome resistance. Conclusion: Our findings establish FGFR1 as a key mediator of alpelisib resistance in ER+ breast cancer. Combining FGFR1 inhibitors with alpelisib-based therapies offers a viable approach for FGFR1-overexpressing tumors.
    Keywords:  AZD4547; FGFR1; PI3K; alpelisib; estrogen receptor; fulvestrant; resistance
    DOI:  https://doi.org/10.20517/cdr.2024.181
  2. iScience. 2025 Jun 20. 28(6): 112526
    STEAP3 promotes triple-negative breast cancer growth through the FGFR1-mediated activation of PI3K/AKT/mTOR signaling.
    Lifang Yuan, Yuhan Bao, Junbao Liu, Ping Sun.
      Triple-negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis and lacks effective targeted therapies. Six-transmembrane epithelial antigen of prostate 3(STEAP3) is specifically overexpressed in TNBC, but its precise role and molecular mechanisms remain unclear. Here, we show that STEAP3 is positively correlated with proliferation markers in TNBC, but not in non-TNBC. Further assays revealed that STEAP3 significantly enhances TNBC cell proliferation, invasion, and metastasis in vitro. Mechanistically, STEAP3 promotes TNBC progression by stabilizing FGFR1 and subsequently activating the PI3K/AKT/mTOR pathway. In xenograft models, STEAP3 knockdown suppressed tumor growth and reduced the expression of proliferation markers, consistent with in vitro findings. These results demonstrate STEAP3 as a key regulator of TNBC progression via FGFR1-mediated PI3K/AKT/mTOR signaling and highlight its potential as a promising therapeutic target.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112526
  3. Front Oncol. 2025 ;15 1568524
    Targeting the leptin receptor promotes MDA-MB-231 cells' metabolic reprogramming and malignancy: the role of extracellular vesicles derived from obese adipose tissue.
    Carol Costa Encarnação, Carolinne Souza Amorim, Victor Aguiar Franco, Luiz Gabriel Xavier Botelho, Ronan Christian Machado Dos Santos, Isadora Ramos-Andrade, Luiz Guilherme Kraemer-Aguiar, Christina Barja-Fidalgo, João Alfredo Moraes, Mariana Renovato-Martins.
       Introduction: Leptin, a key adipokine secreted by adipose tissue (AT), has emerged as a critical mediator linking obesity and breast cancer, both of which are major global health concerns. Elevated leptin levels are detected in the circulation and in extracellular vesicles (EVs) released by adipose tissue, particularly in cases of obesity. These leptin-enriched EVs have been implicated in various stages of tumor progression. In this study, we investigated the effects of leptin within extracellular vesicles (EVs) secreted by obese adipose tissue on the functional properties and metabolism of MDA-MB-231 breast cancer cells, a model for triple-negative breast cancer (TNBC).
    Method: MDA-MB-231 cells were treated with EVs derived from the subcutaneous adipose tissue of eutrophic (EUT EVs) and obese (OB EVs) individuals.
    Results: Our findings revealed that OB EVs induced significant phosphorylation of STAT3, a key signaling molecule in cancer progression, and promoted increased cell migration, dependent on fatty acid oxidation (FAO). This effect was reversed in the presence of a leptin receptor antagonist, highlighting leptin's pivotal role in these processes. Additionally, OB EVs caused metabolic changes, including reduced lactate levels and decreased pyruvate kinase (PK) activity, while increasing glucose-6-phosphate dehydrogenase (G6PDH) activity, suggesting metabolic reprogramming that supports tumor cell survival and proliferation. In addition to metabolic alterations, OB EVs also impacted mitochondrial dynamics. We observed an upregulation of fusion and fission markers and a redistribution of mitochondria toward the cell periphery, which supports migration. Moreover, OB EVs increased the invasive capacity of MDA-MB-231 cells, an effect mediated by matrix metalloproteinase-9 (MMP-9).
    Discussion: Overall, our results highlight how obese adipose tissue modulates breast cancer cell behavior, with leptin-enriched EVs playing a central role in driving migration, metabolic reprogramming, and invasiveness, thereby promoting tumor malignancy. This study underscores the importance of EVs in the obesity-cancer link and offers new insights for therapeutic strategies targeting leptin signaling and EV-mediated communication in breast cancer.
    Keywords:  adipose tissue; breast cancer; extracellular vesicles; leptin; obesity
    DOI:  https://doi.org/10.3389/fonc.2025.1568524
  4. Front Oncol. 2025 ;15 1579423
    Unveiling the impact of lipid metabolism on triple-negative breast cancer growth and treatment options.
    Xin-Xian Cai, Zhe-Zhong Zhang, Xiao-Xiao Yang, Wen-Rui Shen, Liu-Wei Yuan, Xi Ding, Ying Yu, Wen-Yu Cai.
      Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with poor prognosis and limited targeted treatment options. Lipid metabolism plays a pivotal role in the initiation, progression, and metastasis of TNBC by supporting cancer cell energy production, facilitating membrane biosynthesis, and regulating signal transduction. Dysregulation of lipid metabolism promotes tumor cell proliferation and contributes to processes such as epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. Targeting lipid metabolism-such as inhibiting fatty acid synthase (FASN) and lipid metabolic byproducts-has emerged as a promising therapeutic strategy. The integration of multi-omics approaches and advanced imaging technologies can further elucidate the interactions between lipid metabolism and the tumor microenvironment, thereby supporting precision oncology. Future research should explore the role of lipid metabolism in distinct TNBC subtypes, optimize therapeutic strategies, and improve patient outcomes, particularly for those who are unresponsive to conventional treatments.
    Keywords:  cell death; energy metabolism; lipid metabolism; recurrence of metastases; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1579423
  5. Cancer Control. 2025 Jan-Dec;32:32 10732748251347917
    New Insights Into Adipokines and the Tumor Microenvironment in Breast Cancer.
    Xin Ma, Shaofeng Yang, Donghai Li.
      Breast cancer remains the malignant tumor with the highest incidence among female patients globally, and its treatment represents a well-recognized clinical challenge. Recent studies have demonstrated that the tumor microenvironment (TME) exerts a substantial influence on breast cancer progression, whereby alterations in its internal molecular components ultimately impact disease outcomes. Key factors implicated in this process include adipokines and microRNAs (miRNAs). This review provides a detailed description of how different adipocytokines exert specific mechanistic effects on breast cancer cells. By integrating adipokines with miRNAs, the discussion explores their combined roles in the initiation and progression of breast cancer, addressing a previously unaddressed research gap in studies focusing solely on individual adipokines. Furthermore, by examining the interactions between miRNAs and signaling pathways, this analysis offers a holistic perspective on the TME network, thereby fostering new therapeutic insights for breast cancer management.
    Keywords:  adipokines; breast cancer; signaling pathway; tumor microenvironment
    DOI:  https://doi.org/10.1177/10732748251347917
  6. bioRxiv. 2025 May 27. pii: 2025.05.22.655436. [Epub ahead of print]
    LMO2 regulates epithelial-mesenchymal plasticity of mammary epithelial cells.
    Veronica Haro-Acosta, Maria A Juarez, Isobel J Fetter, Andrew Olander, Shaheen S Sikandar.
      Cellular plasticity in mammary epithelial cells enables dynamic cell state changes essential for normal development but can be hijacked by breast cancer cells to drive tumor progression. However, the molecular factors that maintain cellular plasticity through the regulation of a hybrid cell state (epithelial/mesenchymal) are not fully defined. As LMO2 has been previously shown to regulate metastasis, here we determined the role of LMO2 in the normal mammary epithelial cells. Using lineage tracing and knockout mouse models we find that Lmo2 lineage-traced cells persist long-term in the mammary gland, both in the luminal and basal layer but have limited proliferative potential. Lmo2 loss does not impact mammary gland development, but acute deletion decreases in vivo reconstitution. Moreover, LMO2 knockdown in mouse and human mammary epithelial cells (MECs) reduces organoid formation. We find that LMO2 maintains a hybrid cell state in MECs and LMO2 knockdown promotes mesenchymal differentiation. Transcriptional profiling of LMO 2 knockdown cells reveals significant enrichment in the epithelial-mesenchymal transition (EMT) pathway and upregulation of MCAM, a negative regulator of regenerative capacity in the mammary gland. Altogether, we show that LMO2 plays a role in maintaining cellular plasticity in MECs, adding insight into the normal differentiation programs hijacked by cancer cells to drive tumor progression.
    DOI:  https://doi.org/10.1101/2025.05.22.655436
  7. Int J Mol Sci. 2025 May 26. pii: 5101. [Epub ahead of print]26(11):
    HIF-1α-Mediated Disruption of Cellular Junctions: The Impact of Hypoxia on the Tumor Microenvironment and Invasion.
    Michael Springer, Zeynep Aydin Burakgazi, Anastasiia Domukhovska, Ben Nafchi, Michael C Beary, Arielle Acquisto, Juliette Acquisto, Vladyslav Komarov, Madison Jensen, Brandon Gulledge, Maksym Poplavskyi, Md Gias Uddin, Gamal Rayan, Shoshanna N Zucker.
      Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in the processes of tumorigenesis, angiogenesis, metabolic reprogramming, and immune evasion. This review provides a comprehensive examination of the role of HIF-1α in hypoxia and how hypoxia weakens intercellular junctions-including gap junctions, adherens junctions, tight junctions, and desmosomes. The disruption of gap junctions decreases intercellular communication, which alters signal transduction cascades and tumor suppressive properties. Adherens junctions are comprised of proteins that characterize the tissues and link cells to the actin cytoskeleton, whereby their disruption promotes the epithelial-to-mesenchymal transition (EMT). Under hypoxic conditions, the tight junction proteins are dysregulated, altering paracellular transport and cell polarity. In addition, desmosomes provide linkage to intermediate filaments, and hypoxia compromises tissue integrity. Collectively, the influence of hypoxia on cellular junctions promotes tumorigenesis through reducing cell communication, cytoskeletal interactions, and altering signaling pathways. Activation of matrix metalloproteinases (MMPs) further degrades the extracellular matrix and enhances tumor invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1α. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. Furthermore, this review examines current treatments aimed at targeting HIF-1α and explores future directions to enhance treatment efficacy and improve patient outcomes.
    Keywords:  adherens junctions; angiogenesis; desmosomes; gap junctions; hypoxia; matrix metalloproteinases; metastasis; tight junctions; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26115101
  8. Ann Med Surg (Lond). 2025 Jun;87(6): 3635-3659
    Oxygen deprivation in breast cancer: mechanisms, pathways, and implications.
    Emmanuel Ifeanyi Obeagu.
      Hypoxia, a state of reduced oxygen availability, is a defining feature of the tumor microenvironment in breast cancer. It arises from the rapid proliferation of cancer cells, which outpaces the development of adequate vasculature. This oxygen deprivation triggers a cascade of molecular and cellular adaptations that enable tumor cells to survive and thrive under hostile conditions. Key among these is the stabilization of hypoxia-inducible factors, which regulate genes involved in angiogenesis, metabolic reprogramming, immune evasion, and cell survival. Hypoxia significantly influences breast cancer behavior, promoting tumor aggressiveness, therapeutic resistance, and metastatic potential. The hypoxic microenvironment fosters angiogenesis through vascular endothelial growth factor signaling, albeit leading to abnormal and inefficient vasculature. It also reprograms cancer cell metabolism towards glycolysis, supporting survival and growth in oxygen-deprived regions. Furthermore, hypoxia modulates immune responses, suppressing anti-tumor immunity while promoting the recruitment of immunosuppressive cells. These multifaceted effects underscore hypoxia's pivotal role in shaping the clinical trajectory of breast cancer.
    Keywords:  breast cancer; hypoxia; hypoxia-inducible factors; therapeutic resistance; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000003334
  9. Int J Mol Sci. 2025 May 28. pii: 5183. [Epub ahead of print]26(11):
    The Mechanical Properties of Breast Cancer Cells and Their Surrounding Microenvironment.
    Leila Jahangiri.
      Breast cancer is a major health concern for women worldwide, and therefore, understanding various changes acquired by breast cancer cells is relevant to a better comprehension of the disease. One such change includes alterations to the mechanical properties of breast cancer cells. For example, cells with high malignant potential show lower adhesion forces and higher cell deformability. Mechanical forces, including tensile and compressive forces of the cytoskeleton and the extracellular matrix such as integrin, collagen, and the basement membrane, can affect BC cells. These forces alter the properties of cancer cells, drive them towards invasiveness due to different motility and proliferative profiles, and change their microenvironment. This study will focus on the mechanical characteristics of breast cancer cells and the extracellular matrix. Furthermore, changes induced in breast cancer cells following exposure to mechanical forces will be reviewed. Genes that link phenotype to mechanical forces and the implications of these forces for diagnostics and treatment will be discussed.
    Keywords:  breast cancer; extracellular matrix; invasion; mechanical forces
    DOI:  https://doi.org/10.3390/ijms26115183
  10. Sci Rep. 2025 Jun 06. 15(1): 19896
    PTPN2 inhibits TG-induced ERS-initiated TNBC apoptosis through the mitochondrial pathway.
    Yanhe An, Jinxin Lan, Jiaping Tang, Na Luo.
      Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer that portends a poor prognosis and limited treatment. PTPN2 is a member of the non-receptor protein tyrosine phosphatase family that regulates biological processes by dephosphorylating various signaling molecules. Endoplasmic reticulum stress (ERS) plays a dual regulatory role by promoting both survival and apoptosis. This study aims to elucidate the role of PTPN2 in mediating the pro-apoptotic effects of ERS induced by Thapsigargin (TG), and its influence on the fate of TNBC cells, utilizing both loss-of-function and gain-of-function methodologies. Our findings indicate that PTPN2 modulates TG-induced ERS via the IRE1-XBP1 and PERK/EIF2α/ATF-4 signaling pathways. Furthermore, PTPN2 mitigates the TG-induced reduction in cell proliferation and the concomitant increase in apoptosis. Specifically, PTPN2 appears to inhibit several facets of TG-induced apoptosis, including: (1) Ca2+ elevation in mitochondria, (2) the production of reactive oxygen species (ROS), and (3) Bax/Bcl-2 augmentation which dictates mitochondria-mediated apoptosis. Additionally, we observed that the knockdown of PTPN2 enhances TG-induced autophagy; however, our results suggest that autophagy may serve a protective role against TG-induced apoptosis. Consequently, targeting PTPN2 in conjunction with ERS-inducing agents may represent a promising therapeutic strategy for the treatment of TNBC.
    Keywords:  Apoptosis; ERS; PTPN2; TNBC; The mitochondrial pathway
    DOI:  https://doi.org/10.1038/s41598-025-04312-w
  11. bioRxiv. 2025 May 27. pii: 2025.05.22.655615. [Epub ahead of print]
    Hyperglycemic state and fluid shear stress affect metastatic breast cancer cell migration via focal adhesion kinase.
    Brandon D Riehl, Eunju Kim, Taylor Boudreaux, Osaira Ovando, Stephanie Vielmas- Duarte, Suyong Choi, Hamid Band, Lanju Mei, Diganta Dutta, Surabhi Chandra, Jung Yul Lim.
      We tested how the diabetes-related hyperglycemic condition affects the migration of highly metastatic triple-negative breast cancer (TNBC) cells, MDA-MB-231, under a physiological fluid shear environment. MDA-MB-231 cells displayed a significantly enhanced migratory behavior under a high glucose condition (25 mM) specifically when exposed to flow at 15 dyne/cm 2 shear stress. In contrast, the effect of fluid shear was marginal under low glucose (5 mM). Normal epithelial MCF-10A cells, on the other hand, showed increased migration by fluid shear under both low and high glucose conditions. The fluid shear-triggered MDA-MB-231 cell migration under high glucose was significantly abrogated by a focal adhesion kinase (FAK) inhibitor, supporting the mediatory role of FAK in MDA-MB-231 TNBC cell sensing of the high glucose-fluid shear environment during migration. The role of FAK was further demonstrated by the effects of FAK inhibitor on MDA-MB-231 cell migration in scratch wound healing and Boyden chamber migration assays. Our studies provide evidence that high glucose and fluid shear could jointly trigger MDA-MB-231 TNBC cell migration that requires FAK activity. These may provide improved mechanistic insights into how concurrent diabetes may impact the pro-metastatic behavior of breast cancer and suggest the impact of exploring FAK as a relevant therapeutic target.
    DOI:  https://doi.org/10.1101/2025.05.22.655615
  12. bioRxiv. 2025 Jun 06. pii: 2025.06.05.654750. [Epub ahead of print]
    Astrocyte reprogramming drives tumor progression and chemotherapy resistance in agent-based models of breast cancer brain metastases.
    Rupleen Kaur, Rowan Barker-Clarke, Andrew Dhawan.
      Breast cancer brain metastases (BCBM) affect nearly 90,000 patients annually in the United States and carry a significant risk of mortality. As metastatic lesions develop, the unique milieu of the brain microenvironment shapes disease progression and therapeutic response. Among resident brain cells, astrocytes are both the most common, and are increasingly recognized as key regulators of this process, yet their precise role remains poorly defined. Here, we present a hybrid agent-based model (ABM) to simulate tumor-astrocyte interactions on a two-dimensional lattice. In our model, metastatic tumor cells induce phenotypic reprogramming of astrocytes from an antito a pro-metastatic state, thereby enhancing tumor proliferation. We systematically evaluate how variations in astrocyte density, spatial distribution, and chemotherapy impact tumor expansion and spatial morphology, quantified by fractal dimension, lacunarity, and eccentricity. Our simulations reveal that astrocyte reprogramming accelerates tumor progression and contributes to increased morphological complexity and chemotherapeutic resistance.
    DOI:  https://doi.org/10.1101/2025.06.05.654750
  13. Cancers (Basel). 2025 May 27. pii: 1793. [Epub ahead of print]17(11):
    Lactate Is a Major Promotor of Breast Cancer Cell Aggressiveness.
    Maitham A Khajah, Sarah Khushaish, Yunus Luqmani.
      Background: Lactate dehydrogenase (LDH) activity, producing high levels of lactate from pyruvate in cancer cells, is often associated with poor patient prognosis. We previously showed enhanced LDH/lactate levels in estrogen receptor (ER) compared to ER + breast cancer cells; lactate or pyruvate supplementation to ER + cells significantly enhanced their motile ability, while LDHB gene knockout (KO) or treatment with LDH inhibitors reduced the motility of the highly aggressive ER breast cancer cells. Aims: To investigate the molecular mechanisms by which lactate, LDHB KO, or treatment with LDH inhibitors can modulate the motile capabilities of breast cancer cell lines. Methods: KO experiments were performed using siRNA, and global expression was determined by proteomic profiling with Proteome Profiler Human XL Oncology arrays, Western blot, and immunofluorescence. Results: Lactate supplementation to ER + breast cancer cells enhanced expression of vimentin, N-cadherin, and snail, while reducing the expression of JAM-A, E-cadherin, and nectin-4. This expression profile was reversed with LDHB KO in ER cells. LDHB KO, or treatment with LDH inhibitors in ER cells, also reduced the expression of IL-6, IL-8, and MMP-2. The expressions of other markers such as PECAM-1, CCL20, and ENPP-2 were differentially modulated with LDH B KO in de novo ER cells (MDA-MB-231) vs. those that had ER knockout (pII). Conclusions: Our data show a novel role for lactate in modulating the EMT status in breast cancer cells and highlight the important role of lactate in breast cancer motility in part through modulating EMT status and the expression profile of cytokines, adhesion molecules, MMP-2, and nectin-4.
    Keywords:  EMT; LDH; breast cancer; endocrine resistance; lactate; motility; proteomic profiling
    DOI:  https://doi.org/10.3390/cancers17111793
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