bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–04–26
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. PFKP is required for chemoresistant phenotype of breast cancer through modulating the formation of CD133+ cancer stem like cells.
  2. ACSS2 Suppresses Ferroptosis to Drive Breast Cancer Brain Metastasis.
  3. Cyclophosphamide Induces Autophagy-Dependent Ferroptosis Through Promoting ETNK1 Expression in Breast Cancer Cells.
  4. LINC01128 Affects Triple-Negative Breast Cancer Progression Through Targeting miR-32-5p.
  5. NUP62 promotes breast cancer progression and inhibits ferroptosis by stabilizing NRF2 in a KEAP1-dependent way.
  6. Targeting of MARK2, but not other MARKs, suppresses TNBC progression by inhibition of the mutant p53-driven signaling pathway.
  7. Hypoxia-Inducible Factors as Guardians of Cancer Stem Cell Fate: Implications for Novel Therapies.
  8. Nitric oxide-dependent stabilization of vimentin confers chemoresistance in ovarian cancer.
  1. Mol Biomed. 2026 Apr 23. pii: 56. [Epub ahead of print]7(1):
    PFKP is required for chemoresistant phenotype of breast cancer through modulating the formation of CD133+ cancer stem like cells.
    Kai Fang, Yue Ma, Lihua Li, Yan Yue, Hang Ruan, Sidong Xiong.
      Breast cancer is the foremost cause of cancer-related death in women globally, and taxane-anthracycline (TA) combination regimens represent standard frontline chemotherapy. Although widely administered, the pathological complete response rate to TA therapy is less than 30%, and chemoresistance remains a major barrier to effective disease control, frequently leading to relapse and poor survival. Both metabolic reprogramming and tumor microenvironmental remodeling are closely associated with treatment failure, yet how they interact to drive TA resistance remains largely unclear. Here we show that phosphofructokinase platelet (PFKP), a key glycolytic enzyme, is highly expressed in breast cancer. PFKP drives glycolysis and promotes CD133+ cancer stem-like cells (CSLCs) that are inherently TA-resistant. Moreover, PFKP-overexpressing cancer cells stimulate cancer-associated fibroblasts (CAFs), which in turn augment CD133+ CSLC formation via the CXCL16/CXCR6 axis, establishing a feedforward loop that reinforces chemoresistance. These results reveal a previously unappreciated mechanism by which a glycolytic enzyme in cancer cells orchestrates stromal crosstalk to sustain a chemotherapy-refractory niche. By identifying PFKP as a key driver and the PFKP-CSLC-CAF axis as an actionable target, our work moves the field beyond the traditional view of metabolic reprogramming as a cell-autonomous event. Disrupting this axis-for instance, by PFKP inhibition or CXCL16/CXCR6 blockade-may restore TA sensitivity in aggressive basal-type breast cancer, offering a promising strategy to improve long-term outcomes for hard-to-treat patients.
    Keywords:  Breast cancer; Cancer stem-like cells; Cancer-associated fibroblasts; Chemoresistance; Glycolysis; PFKP
    DOI:  https://doi.org/10.1186/s43556-026-00454-z
  2. Cancer Res. 2026 Apr 22.
    ACSS2 Suppresses Ferroptosis to Drive Breast Cancer Brain Metastasis.
    Riley G Young, Emily M Esquea, Lorela Ciraku, Jessica Merzy, Nusaiba N Ahmed, Alexandra N Talarico, Mangalam Karuppiah, Sophia M Medori, Rujula P Warade, Wiktoria Gocal, Alexej Dick, Nicole L Simone, Mauricio J Reginato.
      Brain metastasis in breast cancer patients represents a terminal disease stage, with median survival typically measured in months. Tumors that colonize the brain must adapt to its unique microenvironment, such as high acetate levels. Primary brain tumor cells enhance acetate conversion to acetyl-CoA through phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5), a process regulated by the nutrient sensor O-GlcNAc transferase (OGT). In this study, we showed that brain-metastatic breast cancer cells exhibited elevated O-GlcNAc, OGT, and phosphorylated ACSS2 (Ser267) compared to their parental counterparts. Both OGT and CDK5 were essential for in vivo tumor growth in the brain, and ACSS2 and a phospho-mimetic S267D mutant drove progression of brain metastatic breast cancer. Mechanistically, ACSS2 supported tumor cell survival by suppressing ferroptosis through E2F1-dependent transcription of the anti-ferroptotic protein SLC7A11. Treatment with brain-penetrant ACSS2 inhibitor AD-5584 induced ferroptosis and significantly suppressed breast cancer brain metastatic growth ex vivo and in vivo. Together, these findings identify ACSS2 as a key metabolic regulator of brain-metastatic breast cancer survival and a promising target for ferroptosis-inducing therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3006
  3. Drug Dev Res. 2026 May;87(3): e70289
    Cyclophosphamide Induces Autophagy-Dependent Ferroptosis Through Promoting ETNK1 Expression in Breast Cancer Cells.
    Jiacheng Shen, Aifeng Qiu, Xiaobing Liu, Yuhua Shi, Biao Liu, Lei Li.
      Breast cancer is the most common cancer in females worldwide, and the incidence rate in China has been increasing in recent decades. The treatment of breast cancer with cyclophosphamide (CTX) is one of the cornerstones of combination chemotherapy. However, the mechanisms underlying the anti-tumor effect of CTX is not fully understood. CCK8 assay was employed to detect the IC50 value and viability of breast cancer cell lines (MCF-7 and 4T1). Cell morphology was observed. Tunel assay was carried out to determine cell apoptosis. The content of iron level (Fe2+), malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) was assessed to measure the ferroptosis level. Western blot measured the expression of ETNK1, and autophagy-related proteins (Beclin1 and LC3). The mechanism in vivo was verified in the nude mice model transplanted with MCF7 cells. CTX inhibited cell proliferation, promoted cell apoptosis and ferroptosis in vitro. Inhibition of autophagy could suppress CTX-induced ferroptosis. CTX treatment could increase ETNK1 expression. Downregulation of ETNK1 could reverse the impacts of CTX on cell survival, ferroptosis, and autophagy both in vitro and in vivo. CTX-induced iron death dependent on autophagy in breast cancer cells by promoting the expression of ETNK1.
    Keywords:  ETNK1; autophagy; breast cancer; cyclophosphamide; ferroptosis
    DOI:  https://doi.org/10.1002/ddr.70289
  4. Breast Cancer (Dove Med Press). 2026 ;18 596228
    LINC01128 Affects Triple-Negative Breast Cancer Progression Through Targeting miR-32-5p.
    Min Xiong, Quanjun Yang, Le Cheng, Lili Yu, Yili Hu.
       Objective: To clarify the expression and clinical significance of LINC01128 in triple-negative breast cancer (TNBC), investigate whether it regulates the biological behaviors of TNBC cells by targeting miR-32-5p via the ceRNA mechanism, and explore new therapeutic targets.
    Methods: Tumor tissues and corresponding adjacent normal tissues from 76 TNBC patients were collected, and the patients' clinicopathological data were gathered. Experiments were conducted using the human normal breast epithelial cell line MCF-12F and multiple TNBC cell lines. Quantitative real-time PCR (qPCR) was used to detect the relative expressions of LINC01128 and miR-32-5p; dual-luciferase reporter assay was performed to verify the targeted binding relationship between the two. CCK-8 assay, flow cytometry, and Transwell assay were used to detect cell proliferation, apoptosis, and migration abilities, respectively. Target gene prediction and GO/KEGG enrichment analyses were carried out by combining databases such as miRDB and miRWalk.
    Results: LINC01128 was highly expressed in TNBC tissues and cells (P<0.01), and its high expression was an independent risk factor for advanced TNBC (OR=6.635, P=0.001). miR-32-5p was lowly expressed in TNBC (P<0.01) and showed a significant negative correlation with LINC01128 (r=-0.699, P<0.001), with a direct targeted binding between the two. LINC01128 promoted TNBC cell proliferation and migration and inhibited apoptosis by suppressing miR-32-5p (all P<0.01). The target genes of miR-32-5p were enriched in tumor-related pathways.
    Conclusion: LINC01128 is highly expressed in TNBC and promotes tumor progression by targeting and suppressing miR-32-5p via the ceRNA mechanism, which can serve as a potential molecular marker and therapeutic target for TNBC.
    Keywords:  LINC01128; apoptosis; miR-32-5p; migration; proliferation; triple-negative breast cancer
    DOI:  https://doi.org/10.2147/BCTT.S596228
  5. iScience. 2026 May 15. 29(5): 115484
    NUP62 promotes breast cancer progression and inhibits ferroptosis by stabilizing NRF2 in a KEAP1-dependent way.
    Ziran Qiu, Yu Lin, Shanzheng Chen, Wenqing Cao, Jun Yang, Rui Li, Yuan Chen, Xiaoqing Yao, Senlin Fu, Na Jin.
      Identification of drug resistance drivers of breast cancer (BC) is a multifaceted challenge. Here, we demonstrated that NUP62 is significantly upregulated in BC tissues and cell lines, and its high expression correlates with a poor prognosis. Functional experiments revealed that NUP62 promotes BC cell proliferation, migration, and malignant phenotypes, while inhibiting ferroptosis. Mechanistically, NUP62 competitively binds to KEAP1, disrupting KEAP1-mediated ubiquitination and degradation of NRF2. This stabilization promotes NRF2 nuclear translocation, enhancing the transcription of antioxidant genes and inhibiting ferroptosis. Crucially, eribulin-identified through virtual screening of FDA-approved compounds-selectively inhibited NUP62, destabilizing NRF2 and abrogating its nuclear localization. In vivo, eribulin or NUP62 silencing significantly suppressed tumor growth in xenograft models. Our findings establish the NUP62-KEAP1-NRF2 axis as a master regulator of ferroptosis in BC, positioning eribulin as a promising therapeutic agent for NUP62-high tumors.
    Keywords:  cancer; molecular biology; pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2026.115484
  6. Chin J Nat Med. 2026 Apr;pii: S1875-5364(26)61172-7. [Epub ahead of print]24(4): 414-426
    Targeting of MARK2, but not other MARKs, suppresses TNBC progression by inhibition of the mutant p53-driven signaling pathway.
    Min Zhang, Xilong Zhu, Mengqian Cui, Yinan Guan, Yong Zhang, Stephen J Weiss, Jun Chen, Yongzhong Yao, Rong Fu, Zhaoqiu Wu.
      Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the absence of effective targeted therapies. In this study, we demonstrate that elevated expression of microtubule affinity-regulating kinase 2 (MARK2), but not other MARK family members (MARK1, MARK3, and MARK4), correlates with poor prognosis in TNBC patients. Silencing MARK2 impairs TNBC progression via inhibition of mutant p53 (mutp53) signaling. In contrast, silencing any of the other three MARKs either enhances or does not affect TNBC cell growth or migration and has no impact on mutp53 expression. Notably, direct knockdown of mutp53 recapitulates the effects of MARK2 ablation in TNBC cells, further supporting a functional linkage. Moreover, ectopic expression of either wild-type (WT) MARK2 or its kinase-dead (KD) mutant enhances mutp53 signaling and promotes TNBC progression; however, MARK2 overexpression does not alter wild-type p53 (wtp53) expression or cell growth in luminal breast cancer cells. Significant inverse correlations are also observed between the expression levels of MARK2, THBS1, or HBEGF (two direct target genes of mutp53) and both overall and disease-free survival in TNBC patients harboring mutTP53, whereas no such association exists between MARK2 and survival in breast cancer subtypes expressing wtTP53. MARK2 is predominantly localized in the nucleus of TNBC cells, where it interacts with and stabilizes mutp53 through its UBA and Spacer domains. Consistent with this, MARK2-ΔUBA or MARK2-ΔSpacer mutant proteins fail to bind mutp53 or sustain its signaling, thereby acting as dominant-negative inhibitors that suppress TNBC progression. Collectively, our findings indicate that suppressing MARK2 expression, rather than inhibiting its kinase activity, may represent an effective therapeutic strategy for TNBC with mutTP53.
    Keywords:  Dominant-negative MARK2; MARK2; THBS1 and HBEGF; TNBC progression; mutp53
    DOI:  https://doi.org/10.1016/S1875-5364(26)61172-7
  7. IUBMB Life. 2026 Apr;78(4): e70092
    Hypoxia-Inducible Factors as Guardians of Cancer Stem Cell Fate: Implications for Novel Therapies.
    Qamar Abuhassan, Hamzeh J Al-Ameer, Hani Moslem Ahmed, Jasur Rizaev, Azizbek Togaev, Rasim M Salih, Mohaned Adil.
      Cancer stem cells (CSCs) represent a dynamic, therapy-refractory subpopulation that fuels tumor initiation, metastasis, and relapse through remarkable self-renewal capacity and phenotypic plasticity. Extensive evidence has established that hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key regulators of CSC behavior within the hypoxic tumor microenvironment (TME) across diverse malignancies, including breast cancer, glioblastoma, and colorectal carcinoma. Under hypoxic conditions, HIFs stabilization orchestrates stemness maintenance, epithelial-mesenchymal transition (EMT), immune evasion, and metabolic reprogramming. Concurrently, HIF activity upregulates efflux transporters and anti-apoptotic genes, thereby contributing to resistance against chemotherapy and radiotherapy. This review integrates recent advances in HIF-CSC crosstalk, with particular emphasis on interactions with core pluripotency networks (Oct4, Sox2, Nanog), therapy-induced CSC enrichment, and hypoxia-driven immune suppression. We further highlight current limitations and prospects of HIF-targeted strategies, including isoform-specific inhibitors and combination regimens. By addressing existing knowledge gaps, this work provides a comprehensive framework to guide the development of next-generation therapies aimed at durable CSC eradication and improved clinical outcomes in hypoxia-driven cancers.
    Keywords:  HIF inhibitors; HIFs; cancer stem cell; hypoxia; hypoxia inducible factor
    DOI:  https://doi.org/10.1002/iub.70092
  8. Mol Ther Nucleic Acids. 2026 Jun 16. 37(2): 102924
    Nitric oxide-dependent stabilization of vimentin confers chemoresistance in ovarian cancer.
    Gianmarco Melone, Recep Bayraktar, Hong Zhao, Sean O Hynes, Fidelma Kaar, Adam Freegrove, Jenying Deng, Agne Baseviciene, Ivonne Uzair, Karina Ortega Martinez, Liliana Guzman-Rojas, Maria Florencia Chervo, Mailin Li, Wei Qian, Jianying Zhou, Aireana Phillips, Kristina Diana A Zambo, Fotis Nikolos, Keith S Chan, Christoforos Thomas, Lewis Francis, Jenny C Chang.
      High-grade serous ovarian carcinoma (HGSC) is often diagnosed at an advanced stage and is characterized by an immunosuppressive tumor microenvironment that facilitates disease progression, therapeutic resistance, and poor survival. We recently demonstrated that nitric oxide (NO) blockade enhances the response of metaplastic breast cancer to PI3K inhibition and taxane therapy by reducing S-nitrosylation-mediated activation of the JNK/c-Jun pathway, thereby promoting tumor differentiation, suppressing stemness, and improving survival in patient-derived xenograft models. Here, we demonstrate that inducible nitric oxide synthase (iNOS) is constitutively expressed in HGSC and that pharmacologic inhibition of NO signaling with the pan-NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) enhances cisplatin efficacy by reprogramming the tumor microenvironment. By targeting NO signaling with either L-NMMA or through CRISPR-Cas9-mediated iNOS knockout and iNOS small interfering RNA (siRNA), we impaired epithelial-to-mesenchymal transition (EMT) by inhibiting NO-mediated stabilizing effects on vimentin in both in vitro and in vivo models. Mechanistically, L-NMMA-mediated inhibition of iNOS signaling reduced S-nitrosylation, accelerated vimentin ubiquitination, and promoted its proteasome-dependent degradation. These findings identify iNOS-mediated S-nitrosylation as a key regulator of vimentin stability and EMT and suggest that therapeutic inhibition of NO signaling may increase cisplatin sensitivity in HGSC and improve patient outcomes.
    Keywords:  L-NMMA; MT: Oligonucleotides: Therapies and Applications; S-nitrosylation; chemoresistance; cisplatin; epithelial-mesenchymal transition; high-grade serous ovarian cancer; iNOS; nitric oxide; tumor microenvironment; vimentin
    DOI:  https://doi.org/10.1016/j.omtn.2026.102924
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒28 at 18:43.