bims-merabr 2026-08-16 papers

Cell Signal. 2026 Aug 12. pii: S0898-6568(26)00475-4. [Epub ahead of print] 112817

UNCX/SIN3A-Mediated H4K8 decrotonylation suppresses FOXO3 to drive TNBC progression and docetaxel resistance.

Songfu Shi, Dong Yan, Lixin Zhao, Yihao Zheng, Lingxi Ye, Yongjia Zeng, Linghang Zeng, Fan Wang, Wenjuan Wang, Shumeng Liu.

Triple-negative breast cancer (TNBC) remains a clinically challenging subtype characterized by aggressive behavior and limited treatment options. Though docetaxel remains a cornerstone chemotherapy for TNBC, the frequent emergence of resistance highlights the urgent need to identify novel therapeutic targets. In this study, we report that uncoordinated homeobox (UNCX) is upregulated in docetaxel-resistant breast cancer cells, genomically amplified in breast cancer, and associated with poor survival in breast carcinoma patients. Functional studies revealed that UNCX promotes breast cancer cell proliferation, migration and reduces the docetaxel sensitivity. Mechanistically, UNCX functions as a transcriptional repressor by recruiting the SIN3A complex. Genome-wide profiling indicated that the UNCX/SIN3A complex directly binds to the promoters of tumor-suppressor genes including FOXO3, and represses their transcription by removing histone H4K8 crotonylation (H4K8cr). Additionally, the UNCX/SIN3A complex enhances FOXO3 phosphorylation and inhibits its nuclear translocation, further inhibiting its activity. Notably, SIN3A knockdown, FOXO3 overexpression, or crotonylation restoration effectively reverses UNCX-induced malignant phenotypes. These findings collectively establish the UNCX/SIN3A-H4K8cr-FOXO3 axis as a pivotal epigenetic regulator of TNBC progression and chemoresistance, revealing new avenues for targeted therapeutic development against this aggressive breast cancer subtype.

Keywords: Docetaxel resistance; FOXO3; Histone crotonylation; TNBC; UNCX

DOI: https://doi.org/10.1016/j.cellsig.2026.112817

Int J Mol Sci. 2026 Jul 29. pii: 6787. [Epub ahead of print]27(15):

MicroRNA Signatures of Fulvestrant-Treated Luminal Breast Cancer Cells: Identification of Therapeutic Targets Regulated by miR-374b-5p.

Ayako Nagata, Yuya Tomioka, Ryutaro Yasudome, Hiroko Toda, Takuya Tokunaga, Yuki Nagata, Mayuko Kato, Yoshiaki Shinden, Akihiro Nakajo, Naohiko Seki.

Estrogen receptor (ER)-positive breast cancer (BrCa) accounts for two-thirds of all BrCa cases worldwide. Therefore, ER-targeted endocrine therapy is the standard treatment for this disease. There has been a recent trend towards developing combination therapies using molecularly targeted drugs to improve outcomes. This study aimed to identify therapeutic targets demonstrating efficacy when combined with fulvestrant (a selective ER downregulator/degrader). We generated microRNA (miRNA) signatures from fulvestrant-treated MCF-7 cells by RNA sequencing. From the signature, we evaluated miR-374b-5p because its expression was elevated by fulvestrant treatment in MCF-7 cells. Also, in expression analysis by subtype of BrCa patients, miR-374b-5p expression was suppressed only in luminal BrCa. Ectopic expression assays revealed that miR-374b-5p attenuated the malignant phenotypes of MCF-7 cells. We searched for genes regulated by miR-374b-5p and discovered that 11 (NEK2, NUF2, HMMR, DEPDC1B, FOXM1, ELOVL6, KIF20A, NCAPH, CENPK, FAM83D, and KIAA0101) are closely involved in BrCa molecular pathogenesis. Among these target genes, we focused on forkhead box M1 (FOXM1), a transcription factor regulating cell cycle progression and division. Notably, combination therapy with fulvestrant and a FOXM1 inhibitor significantly suppressed MCF-7 cell proliferation. From the miRNA signature established in this study, we identified antitumor miR-374b-5p and its target genes and used these findings to explore candidate drugs with potential efficacy when combined with fulvestrant.

Keywords: FOXM1; breast cancer; estrogen receptor; fulvestrant; miR-374b-5p; microRNA

DOI: https://doi.org/10.3390/ijms27156787

Redox Biol. 2026 Aug 10. pii: S2213-2317(26)00344-7. [Epub ahead of print]96 104345

Nrf2-dependent reprogramming of brown adipose tissue in orthotopic breast cancer model: implications for altered systemic homeostasis.

Maja Vukobratovic, Jelena Jevtic, Tamara Zakic, Vanja Pekovic-Vaughan, Aleksandra Korac, Bato Korac, Aleksandra Jankovic.

Considering cancer within the framework of systemic redox and metabolic regulation may enhance our understanding of disease progression. However, the relationship between cancer and the host redox-metabolic reprogramming within other tissues remains largely unexplored. Brown adipose tissue (BAT), as an important regulator of whole-body metabolic homeostasis, has been implicated in breast cancer progression. Here, we investigated the redox-metabolic profile of BAT and its reprogramming regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) in mice undergoing breast tumour growth. To this end, we established an orthotopic model of breast cancer in wild-type and in mice lacking functional Nrf2 (Nrf2KO) to investigate the Nrf2-driven structural, metabolic, and redox reprogramming of BAT in response to breast tumour growth (10-400 mg). Our results showed that breast tumour growth induced an early adaptive BAT response, characterised by increased uncoupling protein 1 expression. Nevertheless, in response to advanced breast tumours, BAT showed pronounced downregulation of key glycolytic and pentose phosphate pathway protein expression, particularly in Nrf2KO mice. These changes were accompanied by whitening, attenuated UCP1, decreased fatty acid synthesis protein levels, and disrupted β-oxidation protein expression in BAT from Nrf2KO mice bearing larger breast tumours. Furthermore, breast tumour growth altered the protein expression of antioxidant enzymes in BAT, with Nrf2 critical for maintaining glutathione-dependent antioxidant defence. Collectively, these findings highlight an integrative role for Nrf2 in BAT redox-metabolic homeostasis in the context of breast tumour growth, positioning it as a promising therapeutic target and advancing the understanding of breast cancer as a systemic metabolic disease.

Keywords: Antioxidant defence; Breast cancer; Brown adipose tissue; Metabolism; Nrf2

DOI: https://doi.org/10.1016/j.redox.2026.104345

Cancers (Basel). 2026 Aug 06. pii: 2517. [Epub ahead of print]18(15):

CDCA4 Promotes Lipid Metabolism in Triple-Negative Breast Cancer Through Activation of the SESN2/mTOR/SREBP1 Pathway.

Jia Qi, Ming Cai, Xiaowen Wang, Peng Zhang, Jiani Wang, Jiezhong Wu, Weiling Huang, Wenxuan Wu, Kunpeng Hu, Xiaoyuan Liang.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. The molecular drivers of its progression and metabolic reprogramming remain unclear. Here, we identify cell division cycle-associated 4 (CDCA4) as a novel oncogenic driver in TNBC. Analysis of the TCGA-BRCA dataset, including 1085 breast cancer tissues and 112 normal tissues, showed that CDCA4 expression was significantly upregulated in breast cancer tissues. Subgroup analysis of TCGA-BRCA samples further showed higher CDCA4 expression (fold change = 1.707) in TNBC than in non-TNBC samples [TNBC, n = 116; non-TNBC, n = 984]. Survival analysis demonstrated that high CDCA4 expression was associated with poorer overall survival, with a hazard ratio of 1.54 (log-rank p = 0.0053). Functional assays demonstrated that CDCA4 knockdown suppresses proliferation, migration, invasion, and tumor growth in vitro and in vivo, whereas overexpression exerts opposite effects. RNA-sequencing revealed that CDCA4-regulated genes are enriched in lipid metabolism and mTOR signaling pathways. Mechanistically, CDCA4 depletion reduces intracellular lipids and the expression of lipogenic enzymes (FASN, ACC1). We show that CDCA4 activates mTOR and increases the nuclear active form of SREBP1, enhancing its promoter occupancy. Pharmacological mTOR inhibition reverses CDCA4-induced malignancy and metabolic alterations. Furthermore, Our findings suggest that SESN2 may contribute to CDCA4-mediated activation of mTOR signalling. SESN2 knockdown attenuates mTOR signaling and negates the pro-tumorigenic effects of CDCA4 overexpression. Collectively, these findings demonstrate that CDCA4 drives TNBC progression and lipid reprogramming via the SESN2/mTOR/SREBP1 axis, positioning CDCA4 as a potential prognostic biomarker and therapeutic target.

Keywords: CDCA4; lipid metabolism; mTOR signaling; triple-negative breast cancer

DOI: https://doi.org/10.3390/cancers18152517

Biochim Biophys Acta Rev Cancer. 2026 Aug 13. pii: S0304-419X(26)00156-3. [Epub ahead of print] 189684

Drug resistance in breast cancer brain metastasis: mechanisms and therapeutic strategies.

Paromita Sarker, Shreyas S Rao.

Brain-metastatic breast cancer (BMBC) is a severe complication of advanced breast cancer, affecting 15-30% of metastatic patients, particularly those with HER2-positive or triple-negative subtypes, and is associated with dismal prognosis and median survival under 12 months. Therapeutic resistance, driven by the central nervous system's sanctuary role, poses a major barrier to effective treatment, often resulting in discordant intracranial versus extracranial responses. This comprehensive review highlights BMBC resistance mechanisms, drawing from preclinical models, clinical studies, and genomic analyses. Key drivers include genetic/epigenetic alterations, BBB-mediated drug exclusion via efflux transporters, and microenvironmental interactions with astrocytes and immune cells that promote survival signaling. Additional factors encompass cancer stem cell plasticity/dormancy enabling therapy evasion, metabolic reprogramming and extracellular matrix remodeling that shields tumor from drugs. We highlight how these interconnected pathways create a protective niche for metastatic cells. Promising strategies to overcome resistance include BBB-penetrant agents, antibody-drug conjugates, nanomedicine, and combination therapies targeting the tumor microenvironment and epigenetics. By integrating mechanistic insights with translational opportunities, this review emphasizes the potential for personalized, multi-targeted approaches to improve patient outcomes in BMBC.

Keywords: Blood–brain barrier; Brain metastatic breast cancer; Chemotherapy resistance; Drug resistance; Targeted-therapy resistance; Tumor microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2026.189684