bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–01–25
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. ZNF384-regulated SLC31A1 expression promotes tumor proliferation and invasion in breast cancer.
  2. Positive feedback regulation between USP8 and Hippo/YAP axis drives triple-negative breast cancer progression.
  3. Leptin Drives Breast Cancer Aggressiveness Acting Through the Activation of the NCOA1/STAT3 Pathway.
  4. Targeting the UFL1-AKT cascade suppresses triple-negative breast cancer progression.
  5. The UFL1-AKT positive feedback loop promotes breast cancer progression by enhancing lipid synthesis.
  6. ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.
  7. Mechanisms of DDR1 in Reinforcing the Resistance to Radiotherapy in Breast Cancer Through the AMPK/SIRT1/PGC-1α Pathway.
  8. Targeting Estrogen Pathways in Breast Cancer: A Review of Current Therapies and Emerging Strategies.
  1. Mol Cell Biochem. 2026 Jan 19.
    ZNF384-regulated SLC31A1 expression promotes tumor proliferation and invasion in breast cancer.
    Tianzi Hong, Wenlian Li, Qingwei Wang, Zeyi Ye, Yueqin Xu, Bo Yang, Jiaxing Chen, Weibin Lian, Chuan Wang.
       BACKGROUND: SLC31A1, a copper transporter, has been implicated in copper metabolism processes. This study aims to explore the function and potential regulatory mechanisms of SLC31A1 in breast cancer.
    METHODS: The TCGA database was utilized to analyze SLC31A1 expression across various cancer types. SLC31A1 expression in breast cancer tissues was validated in an independent cohort of 80 paired breast cancer and adjacent normal tissues. SLC31A1 expression was manipulated in MCF-7 and BT-549 breast cancer cells using shRNA and overexpression vectors. Cell proliferation, colony formation, and invasion assays were performed to assess the functional consequences of SLC31A1 manipulation. ZNF384, a potential transcription factor for SLC31A1, was identified through bioinformatics analysis, and its binding to the SLC31A1 promoter was confirmed using dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP).
    RESULTS: SLC31A1 expression was significantly elevated in breast cancer tissues, and high expression was associated with poor prognosis. SLC31A1 promoted cell viability, colony formation, and invasion. ZNF384 was identified as a transcription factor that regulates SLC31A1 expression, and its overexpression enhanced SLC31A1 expression, while knockdown of ZNF384 inhibited breast cancer cell proliferation and invasion. ChIP assays confirmed a direct interaction between ZNF384 and the SLC31A1 promoter.
    CONCLUSION: SLC31A1 plays a crucial role in the proliferation and invasion of breast cancer cells, and its expression is regulated by ZNF384. These findings highlight SLC31A1 as a potential therapeutic target and suggest that modulation of copper metabolism may offer novel strategies for breast cancer treatment.
    Keywords:  Biomarkers; Breast cancer; Cell proliferation; Copper metabolism; Invasion; SLC31A1; ZNF384
    DOI:  https://doi.org/10.1007/s11010-025-05460-3
  2. Cell Death Dis. 2026 Jan 21.
    Positive feedback regulation between USP8 and Hippo/YAP axis drives triple-negative breast cancer progression.
    Xin Li, Penghe Yang, Tianshi Wang, Peng Su, Chenmiao Zhang, Shen Fangyu, Huijie Yang, Jian Zhu, Xiaodong Tan, Ting Zhuang.
      The hyper-activation of the Hippo/YAP axis was observed in triple-negative breast cancer (TNBC), which was crucial for tumor progression. The over-activation of YAP in TNBC remains unexplained, despite the continued functionality of the inhibitory phospho-cascade. Recently, studies revealed that the ubiquitin modifications of YAP also play important roles in the Hippo/YAP axis and cancer progression. In order to understand the potential mechanisms of ubiquitination and deubiquitination process in YAP function, we carried out siRNA screening for critical deubiquitinases in TNBC. Via the deubiquitinases (DUB) library, we identified Ubiquitin Specific Peptidase 8 (USP8) as an important effector in YAP function and TNBC progression. Inhibition of USP8 hampered TNBC progression via Hippo signaling. Clinical data revealed that USP8 expression correlated with YAP protein level and poor survival in TNBC patients. Biochemical evaluations revealed that USP8 has the ability to connect with YAP and suppress K48-linked polyubiquitination, thereby enhancing the stability of YAP. Interestingly, YAP directly binds to the USP8 promoter region, enhancing its transcription in TNBC. Our study revealed a forward feedback loop between USP8 and Hippo signaling in TNBC, indicating USP8 as a potential therapeutic drug targets in TNBC.
    DOI:  https://doi.org/10.1038/s41419-025-08356-8
  3. Med Sci (Basel). 2026 Jan 08. pii: 32. [Epub ahead of print]14(1):
    Leptin Drives Breast Cancer Aggressiveness Acting Through the Activation of the NCOA1/STAT3 Pathway.
    Khouloud Ayed, Amal Gorrab, Hichem Bouguerra, Rym Akrout, Sami Zekri, Wassim Y Almawi, Rahma Boughriba, Khalil Choukri, Dhouha Bacha, Alessandra Pagano, Jean-François Louet, Hervé Kovacic, Mounia Tannour-Louet, Asma Gati.
      Background/Objectives: Obesity-associated hyperleptinemia has been linked to breast cancer (BC) progression via mechanisms that remain incompletely understood. This study explores the role of leptin and its receptor (LEPR) in facilitating BC cell proliferation, migration, epithelial-mesenchymal transition (EMT), and STAT3 signaling pathway activation. Methods: We analyzed gene expression and survival data from TCGA BRCA dataset. MCF-7 and MDA-MB-231 BC cells were exposed to leptin at 10 ng/mL (lean-associated levels) and 100 ng/mL (elevated levels linked to obesity). MTT assays, colony formation tests, wound-healing and tumor spheroid dissemination experiments evaluated cell proliferation and migration. Immunofluorescence and Western blot analysis assessed changes in EMT markers and cytoskeletal alterations, while Western blotting and qPCR assessed STAT3 and NCOA1 expression and activation levels. Results: Elevated LEPR expression was linked with unfavorable prognosis in BC patients. Higher doses of leptin (100 ng/mL) significantly enhanced cellular proliferation rates and migratory capabilities, in both cell lines, and promoted EMT characteristics marked by downregulated E-cadherin and cytoskeleton structural changes. Whereas heightened JAK2/STAT3 signaling correlated with elevated leptin dosages, STAT3 inhibition using AG490 reversed leptin-induced migration while reinstating E-cadherin levels to baseline. Furthermore, leptin upregulated NCOA1, an essential STAT3 coactivator, facilitating increased expression of Cyclin D1 and VEGF target genes. Clinical positive relationships were seen between LEP/LEPR expressions and NCOA1 levels and between NCOA1 and various gene signatures related to STAT3/P-STAT3 within BC specimens. Conclusions: Obesity-associated hyperleptinemia enhances aggressiveness in BC through a mechanism involving LEPR-mediated activation pathways encompassing NCOA1/STAT3, which drive proliferation, migration, and EMT. This assigns a potential therapeutic utility for obesity-related advancements found within BC pathology.
    Keywords:  breast cancer; epithelial–mesenchymal transition; leptin; obesity; tumor migration
    DOI:  https://doi.org/10.3390/medsci14010032
  4. Nat Commun. 2026 Jan 20. 17(1): 613
    Targeting the UFL1-AKT cascade suppresses triple-negative breast cancer progression.
    Xiao Yang, Yalei Wen, Xiuqing Ma, Shengying Qin, Yixia Liu, Jiaqi Chen, Haoxing Zhang, Colin R Goding, Rutao Cui, Tongzheng Liu.
      Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease with limited therapies. While UFL1-mediated UFMylation has been implicated in various diseases, its role in TNBC remains not fully understood. Here, we demonstrate that AKT1 directly interacts with UFL1 and undergoes UFMylation at Lys189/276/297. This modification enhances AKT phosphorylation and activation, promoting tumor growth and chemoresistance in TNBC. In turn, AKT phosphorylates UFL1 at Thr426, establishing a positive feedback loop that sustains high activity of both pro-oncogenic regulators in TNBC. Disrupting the UFL1-AKT interaction using the specific peptide PDAU-TAT significantly inhibits TNBC progression both in vitro and in vivo. Clinically, elevated pT426 UFL1 correlates with high pAKT in TNBC specimens. These findings uncover a crucial UFL1-AKT positive feedback loop that drives TNBC progression and suggest that targeting this axis could offer a promising therapeutic strategy for TNBC and potentially other aggressive cancers characterized by upregulated UFL1 and AKT activation.
    DOI:  https://doi.org/10.1038/s41467-026-68493-2
  5. Nat Commun. 2026 Jan 20. 17(1): 614
    The UFL1-AKT positive feedback loop promotes breast cancer progression by enhancing lipid synthesis.
    Fei Meng, Yating Du, Junjie Liang, Huiyan Li, Jingjing Wang, Kexin Tang, Ruixue Kong, Huanran Sun, Tingting Yin, Junru Qin, Xiaomeng Yang, Changliang Shan, Min Liu, Guiwen Yang, Jichun Zhang, Yijie Wang, Jun Zhou, Yan Chen.
      UFMylation, a ubiquitin-like modification, is crucial for cellular processes and is linked to human diseases, including cancer. However, its role in cancer remains unclear. Here, we report that UFL1 promotes breast tumor growth by remodeling lipid metabolism. Mechanistically, UFL1 interacts with and UFMylates AKT, enhancing its localization at the endoplasmic reticulum and phosphorylation by PDK1 and mTORC2, thereby increasing AKT-mediated lipid synthesis. Moreover, AKT phosphorylates UFL1, boosting its activity. Thus, UFL1 and AKT form a positive feedback loop, accelerating lipid synthesis and breast tumor growth. Clinically, UFL1 levels are increased in human breast tumors and are associated with poor clinical outcomes in breast cancer patients. Importantly, UFMylation inhibitors sensitize breast cancer cells to AKT inhibitors and anticancer drugs. Our findings reveal a critical role for UFMylation in lipid metabolism and identify the UFL1-AKT axis as a potential therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1038/s41467-026-68492-3
  6. Cancer Res. 2026 Jan 22.
    ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.
    Shanchun Chen, Chao Chang, Xiaoqi Liu, Rui Wang, Yongcan Liu, Die Meng, Boxuan Wang, Yuhang Hai, Chaoqun Deng, Yanran Tong, Xiaojiang Cui, Siyang Wen, Guobing Yin, Manran Liu.
      Solid tumors frequently preferentially metastasize to specific organs. Metabolites within metastatic niches have emerged as critical regulators of organotropic metastasis. Here, we found that palmitic acid (PA) accumulated in both pre- and macro-metastatic lung niches. Lung-preferential metastatic breast cancer (LM-BC) cells secreted exosomal USP47 that was taken up by lung-resident alveolar type II epithelial cells (AT2) and enhanced fatty acid synthesis via YAP activation, resulting in PA enrichment and subsequent lung metastasis. ACSL5 in LM-BC cells facilitated PA adaptation by inducing COX2-mediated PGE2 accumulation and subsequent activation of the PI3K/AKT and ERK signaling pathways through EP4, which promoted cell survival and lung metastasis. Moreover, ACSL5 boosted levels of palmitoyltransferases, further enhancing COX2 expression, which could be inhibited by the palmitoylation inhibitor 2-bromopalmitate (2-BP). Notably, the enrichment of PA, accumulation of PGE2, and activation of the ACSL5/COX2/EP4 axis in lung metastases of BC patients correlated with poorer clinical outcomes. Limiting PA intake or targeting the ACSL5/COX2/EP4 axis enhanced paclitaxel efficacy in a breast cancer mouse model. Collectively, these findings highlight the critical role of PA and ACSL5/COX2/EP4 signaling in lung metastasis, which can act as promising targets for enhancing the efficacy of chemotherapy in BC patients with lung metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0866
  7. Biochem Genet. 2026 Jan 20.
    Mechanisms of DDR1 in Reinforcing the Resistance to Radiotherapy in Breast Cancer Through the AMPK/SIRT1/PGC-1α Pathway.
    Shuai Wang, Yongjie Chen, Jie Wei, Haixia Wu, Jing Li.
      Breast cancer (BC) is the leading cause of cancer mortality in women. The emergence of resistance to radiotherapy (RT) is a great challenge for BC treatment. Discoidin domain receptor 1 (DDR1) can modulate the proliferation, migration, and apoptosis of cancer cells, but its role in RT of BC has not been illuminated. This project evaluated the expression of DDR1 in BC based on single-cell RNA sequencing data. We established RT-resistant strains through radiation and detected the expression of DDR1 using qPCR. The proliferation and apoptosis abilities of BC cells were evaluated using CCK-8, colony formation assay, and flow cytometry. Western blot and IHC were applied to detect the levels of proteins related to the AMPK/SIRT1/PGC-1α pathway. The effect of the DDR1-mediated pathway on resistance to RT in BC was explored in combination with an AMPK inhibitor. DDR1 was highly expressed in BC. In vitro experiments demonstrated that knocking down DDR1 repressed the viability of BC cells during RT, curbed cell proliferation, facilitated apoptosis, and elevated the levels of p-AMPK, SIRT1, and PGC-1α proteins. The addition of an AMPK inhibitor reversed the effects of DDR1 knockdown on cell proliferation and apoptosis. In vivo experiments showed that knocking down DDR1 inhibited tumor growth, and the inhibitory effect was stronger when combined with radiation therapy. This study revealed that the upregulation of DDR1 in BC may reinforce RT resistance by modulating the AMPK/SIRT1/PGC-1α pathway, thus providing a new therapeutic target for improving the sensitivity of BC to RT.
    Keywords:  AMPK/SIRT1/PGC-1α; Breast cancer; DDR1; Radiotherapy resistance
    DOI:  https://doi.org/10.1007/s10528-025-11314-w
  8. Cell Biochem Funct. 2026 Jan;44(1): e70166
    Targeting Estrogen Pathways in Breast Cancer: A Review of Current Therapies and Emerging Strategies.
    Maitri Dabhi, Ishvarchandra Parmar, Chandrakant Bonde.
      Breast cancer continues to be the most commonly diagnosed cancer among women worldwide, with estrogen receptor-positive (ER +) types making up the largest portion. At the heart of this subtype is the estrogen signaling pathway, especially the estrogen receptor alpha (ERα), which plays a major role in the development, growth, and response to these cancers. This review takes a close look at the structure and function of estrogen receptors and how they influence cancer progression. We explore current treatment strategies-including well-known drugs such as Tamoxifen and Fulvestrant, as well as aromatase inhibitors-and explain how these therapies work and why resistance sometimes develops. This review also dives into newer, more targeted options, such as HER2 inhibitors, CDK4/6 blockers, and drugs that interfere with the PI3K/AKT/mTOR pathway. These treatments are changing the game for many patients. In addition, the review highlights exciting progress in drug design, showing how researchers are improving the precision and effectiveness of cancer medications through innovations in medicinal chemistry. Antibody-drug conjugates (ADCs) are being developed to deliver powerful drugs directly to cancer cells with fewer side effects. This article also looks at emerging approaches, like oral estrogen receptor degraders (SERDs), combination therapies, and precision medicine techniques that tailor treatment based on each patient's unique genetic profile. Altogether, these developments represent a major step forward in our understanding and treatment of ER+ breast cancer.
    Keywords:  CDK4/6 inhibitors; HER2 inhibitors; PI3K/Akt/mTOR pathway inhibitors; aromatase inhibitors; breast cancer; estrogen receptor
    DOI:  https://doi.org/10.1002/cbf.70166
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒25 at 0:15.