bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–09–20
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. In vivo CRISPR screening links NFKB1 to endocrine resistance in ER+ breast cancer.
  2. Bone marrow adipose tissue: fueling breast cancer bone metastasis via pro-tumor mechanisms and novel therapeutic targets.
  3. ZEB1 directly activates IL-6 to promote triple-negative breast cancer stemness in an epigenetically constrained context.
  4. Inhibition of histone acetyltransferase KAT7 suppresses proliferation and migration of breast cancer cells.
  5. Adipose-mimetic granular hydrogels uncover biophysical cues driving breast cancer invasion.
  6. USP38 promotes breast cancer immune evasion and malignant progression by deubiquitinating and stabilizing PD-L1.
  1. Endocr Relat Cancer. 2026 Sep 14. pii: ERC-25-0463. [Epub ahead of print]
    In vivo CRISPR screening links NFKB1 to endocrine resistance in ER+ breast cancer.
    Cancan Lyu, Samuel D Hall, Mark A Stamnes, Songhai Chen.
      Resistance to endocrine therapy (ET) remains a major clinical challenge in the treatment of estrogen receptor-positive (ER+) breast cancer, underscoring the need for novel therapeutic targets. To identify genetic drivers of ET resistance, we conducted an in vivo genome-wide CRISPR-Cas9 screen in MCF7 cells implanted into ovariectomized nude mice under estrogen-deprived conditions. Despite the bottlenecks inherent to in vivo pooled screening, recurrent enrichment analysis identified NFKB1 as a candidate regulator of estrogen-independent tumor progression. Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro and in vivo. Mechanistically, transcriptomic and biochemical analyses revealed that NFKB1 deficiency activated canonical NF-κB signaling, leading to inflammatory gene induction and enhanced ER signaling. Furthermore, pharmacologic inhibition of NF-κB signaling restored ET sensitivity in NFKB1-deficient cells. Analysis of TCGA breast cancer datasets revealed reduced NFKB1 expression in luminal breast tumors, whereas expression of other NF-κB family members was largely unchanged. Further analysis showed that low NFKB1 expression was associated with poorer clinical outcomes in patients with ER+ breast cancer. Collectively, these findings identify NFKB1 as a negative regulator of NF-κB signaling and endocrine resistance in ER+ breast cancer and provide mechanistic evidence linking NF-κB activation to ligand-independent ER signaling. Our results support further investigation of NFKB1 as a candidate biomarker and of NF-κB pathway inhibition as a potential therapeutic strategy in endocrine therapy-resistant breast cancer. These findings also illustrate the utility of in vivo CRISPR screening for identifying candidate regulators of endocrine resistance in breast cancer.
    Keywords:  ER+ breast cancer; Endocrine therapy resistance; In vivo CRISPR-Cas9 Screening; NF-κB signaling; NFKB1
    DOI:  https://doi.org/10.1530/ERC-25-0463
  2. Clin Exp Metastasis. 2026 Sep 17. pii: 48. [Epub ahead of print]43(5):
    Bone marrow adipose tissue: fueling breast cancer bone metastasis via pro-tumor mechanisms and novel therapeutic targets.
    Mengyao Guo, Bangxi Xu, Run Xu, Zeyang Miao, Peng Luo, Guanwu Li.
      Bone metastasis remains a major source of morbidity and mortality in breast cancer. Bone marrow adipose tissue (BMAT) is an active but incompletely defined component of the metastatic niche. This review uses an evidence-tiered framework to integrate four questions: how bone marrow adipocytes exchange lipids and signals with tumor cells; which observations are specific to breast cancer in bone; how broader bone-microenvironment and cross-cancer findings inform biological plausibility; and whether anticancer therapy reshapes BMAT in ways that could influence residual disease. Direct breast cancer evidence supports colonization of adipocyte-rich human bone explants and links adipocyte-derived signals with tumor migration, whereas several metabolic, dormancy, immune, and senescence pathways remain supported mainly by animal, in vitro, or other-cancer studies. Tumor cells, rather than bone marrow adipocytes, can increase fatty-acid transport, activation, and oxidation in response to adipocyte-derived lipids. Chemotherapy and aromatase inhibition can increase marrow adiposity, alter stromal lineage commitment, and promote bone loss; however, a direct causal pathway from treatment-induced BMAT expansion to breast cancer persistence, resistance, or relapse has not been established clinically. Accordingly, we distinguish documented treatment effects from proposed tumor consequences and separate established bone-directed therapy from experimental BMAT-targeted approaches. This framework positions BMAT as a testable and potentially modifiable niche component while avoiding the assumption that all adipocyte-rich marrow states are uniformly pro-metastatic.
    Keywords:  Bone marrow adipose tissue; Bone metastasis; Breast cancer; PPARγ; Therapeutic resistance
    DOI:  https://doi.org/10.1007/s10585-026-10431-z
  3. Front Oncol. 2026 ;16 1929305
    ZEB1 directly activates IL-6 to promote triple-negative breast cancer stemness in an epigenetically constrained context.
    Weiyue Zhang, Yifan Zhou, Wei Ma, Huimin Jiang.
      ZEB1 is a key driver of breast cancer pathogenesis and therapy resistance, largely through its ability to promote cancer stem cells (CSCs). Although tumor-secreted cytokines such as IL-6 are known to support tumor progression, how their expression is regulated by upstream transcriptional factors such as ZEB1 remains incompletely understood. Here, we identify IL-6 as a direct transcriptional target of ZEB1 and reveal an epigenetic dimension associated with this regulation. Mechanistically, ZEB1 binds to specific E2-box elements within the IL-6 promoter and activates its transcription. The IL-6 promoter exhibits local DNA methylation, and ZEB1-dependent IL-6 expression was further enhanced by DNA methyltransferase and histone deacetylase inhibitors, suggesting that the local epigenetic context constrains IL-6 transcription. ZEB1 overexpression was also accompanied by enrichment of the active histone marks H3K27ac and H3K4me3 at the IL-6 promoter, consistent with a more transcriptionally permissive local chromatin state. Functionally, the ZEB1-induced IL-6 expression enhanced CSC-associated properties in vitro and tumor-initiating capacity in vivo. Conversely, IL-6 knockdown attenuated ZEB1-induced CSC-associated phenotypes, whereas pharmacological IL-6 neutralization reduced xenograft burden and CSC-associated populations in vivo. Collectively, our findings establish the ZEB1-IL-6 axis as an important regulator of triple-negative breast cancer (TNBC) stemness and indicate that ZEB1-dependent IL-6 activation is influenced by the local epigenetic context. These findings support further investigation of the ZEB1-IL-6 axis as a potential therapeutic target in ZEB1-high TNBC.
    Keywords:  IL-6; ZEB1; cancer stem cells; epigenetic regulation; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2026.1929305
  4. Front Oncol. 2026 ;16 1893745
    Inhibition of histone acetyltransferase KAT7 suppresses proliferation and migration of breast cancer cells.
    Wei Du, Xiaoyu Xiao, Jiaxin Zhang, Zhongxin Shi, Minlan Yang.
       Background: Lysine acetyltransferase 7 (KAT7), also known as HBO1 or MYST2, is highly expressed in multiple cancers. This study aims to explore the expression patterns of KAT7 in breast cancer and its impact on phenotypes of breast cancer cells.
    Methods: The expression of KAT7 and the overall survival of patients were analyzed using the online bioinformatics platform GEPIA2. Immunohistochemistry was applied to detect KAT7 protein expression in breast cancer specimens (94 breast cancer tissues and 12 adjacent normal tissues). KAT7 shRNA plasmids were used to inhibit KAT7 expression in MCF-7 and MDAMB231 cells, and this inhibition was verified by western blot analysis. Cell counting kit-8 (CCK8), colony formation, and transwell migration assays were employed to assess the proliferation and migration of breast cancer cells.
    Results: KAT7 was highly expressed in breast cancer and correlated with poor patient prognosis. KAT7 expression was significantly higher in breast cancer than in adjacent non-cancerous tissue. 67 of 94 breast cancer samples tested positive for KAT7. KAT7 was significantly negatively correlated with estrogen receptor (ER), progesterone receptor (PR), and Ki67, and was significantly positively correlated with human epidermal growth factor receptor 2 (HER2). KAT7 expression is strongly associated with tumor subtypes. Inhibition of KAT7 significantly suppressed growth, clonogenic formation, and migration in MCF-7 and MDAMB231 cells.
    Conclusions: Our findings demonstrate that KAT7 was highly expressed in breast cancer, and inhibition of KAT7 suppressed proliferation and migration of breast cancer cells.
    Keywords:  KAT7; breast cancer; migration; proliferation; subtypes
    DOI:  https://doi.org/10.3389/fonc.2026.1893745
  5. Cell Biomater. 2026 Aug 18. pii: 100411. [Epub ahead of print]2(8):
    Adipose-mimetic granular hydrogels uncover biophysical cues driving breast cancer invasion.
    Brianna K Knode, Garrett F Beeghly, Brittany E Schutrum, Dong Wang, Yitong Zheng, Alice Battistella, Ruchi Goswami, Chi-Yong Eom, Irina Kopyeva, Aline Bozec, Jochen Guck, Nozomi Nishimura, Salvatore Girardo, Corey S O'Hern, Claudia Fischbach.
      Breast cancer cells invade collagen type I-rich mammary adipose tissue during initial stages of metastasis, but how adipocyte mechanics regulate this process remains unclear. To elucidate these connections, we quantified the size and stiffness of primary adipocytes and replicated these properties using tunable polyacrylamide (PAAm) beads. Subsequently, we embedded these beads into type I collagen to form 3D granular hydrogels mimicking native adipose tissue architecture. Bead-embedded hydrogels demonstrated increased breast cancer cell invasion and collagen fiber organization relative to beadless controls, and cells invaded more readily in systems with decreased bead stiffness. Similarly, Discrete Element Method simulations revealed that soft beads promoted invasion by deforming in response to confined cancer cell migration. These trends were validated in vivo via intravital imaging of murine mammary tumors. Collectively, our data suggest that adipocyte mechanics regulate breast cancer invasion by coordinating both matrix architecture and cellular confinement.
    Keywords:  ECM architecture; TME mechanics; adipose modeling; breast cancer; granular hydrogel
    DOI:  https://doi.org/10.1016/j.celbio.2026.100411
  6. Mamm Genome. 2026 Sep 18. pii: 107. [Epub ahead of print]37(1):
    USP38 promotes breast cancer immune evasion and malignant progression by deubiquitinating and stabilizing PD-L1.
    Dongqin Liu, Zijun Yang, Chunrun Qi, Wanqing Jin, Weiwei Shao.
      Breast cancer (BC) represents the most common malignancy among women worldwide. Immune evasion serves as a critical factor for treatment resistance and recurrence metastasis. For USP38, a member within deubiquitinating enzyme family, its expression pattern, biological function, and regulatory mechanism on tumor immune microenvironment in BC lacked systematic investigation. TIMER and UALCAN databases were used to analyze USP38 expression profile. Forty pairs BC tissue and cell lines were collected for validation. Knockdown/overexpression models were constructed. CCK-8, Transwell, co-immunoprecipitation, ubiquitination analysis, CD8 + T cell co-culture, and in vivo tumor‑bearing experiments were employed to explore function and mechanism. USP38 was highly expressed in BC tissues and cells. USP38 knockdown inhibited proliferation, migration, and invasion. Mechanistically, USP38 directly bound PD-L1 and removed its ubiquitination modification, enhancing PD-L1 stability. USP38 knockdown activated CD8 + T cell function, promoted IFN-γ and granzyme B secretion, and enhanced anti-tumor immunity. In vivo USP38 knockdown suppressed tumor growth, whereas PD-L1 overexpression reversed this effect. USP38 stabilizes PD-L1 through deubiquitination, inhibits CD8 + T cell-mediated anti-tumor immunity, and promotes immune evasion and malignant progression in BC.
    DOI:  https://doi.org/10.1007/s00335-026-10277-6
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