bims-merabr 2026-10-18 papers

Transl Oncol. 2026 Oct 16. pii: S1936-5233(26)00409-2. [Epub ahead of print]74 103073

The CARM1-YIPF2 axis drives breast cancer progression and predicts poor prognosis.

Xitao Gao, Shuchang Zhang, Wei Peng, Kun Xu.

OBJECTIVE: To investigate the roles of CARM1 and its regulatory effect on YIPF2 in breast cancer progression.
METHODS: Breast cancer cells were transfected with CARM1 siRNA to knock down CARM1 expression. Cell proliferation, apoptosis, migration, and invasion were assessed using EdU, CCK-8, Annexin V/PI flow cytometry, wound-healing, and transwell assays, respectively. Co-expression of CARM1 and YIPF2 was evaluated using the GEPIA database and validated by qRT-PCR. Co-immunoprecipitation (Co-IP) was performed to assess the association between CARM1 and YIPF2, and asymmetric dimethylarginine (ADMA) signals in YIPF2 immunoprecipitates were assessed. Rescue experiments were performed following YIPF2 overexpression. In vivo studies were conducted to examine the anti-tumor effects of CARM1 inhibition.
RESULTS: We found that CARM1 was upregulated in breast cancer patients and cell lines. Higher CARM1 expression was associated with poorer survival. CARM1 knockdown inhibited proliferation, colony formation, migration, and invasion of breast cancer cells, and induced apoptosis. The correlation analysis indicated that CARM1 and YIPF2 were positively co-expressed. Co-IP experiments supported an association between CARM1 and YIPF2. CARM1 knockdown reduced the ADMA signal in YIPF2 immunoprecipitates, consistent with CARM1-dependent YIPF2 methylation. In addition, elevated YIPF2 predicted worse survival outcomes in breast cancer patients. Overexpression of YIPF2 partially rescued the suppression of tumor progression induced by CARM1 knockdown. Finally, tumors derived from sh-CARM1 cells were markedly smaller than those from control cells.
CONCLUSION: Collectively, our findings support a role for CARM1 in breast cancer progression and provide evidence of its association with YIPF2 and CARM1-dependent YIPF2 methylation, offering insights into the CARM1-YIPF2 regulatory axis and potential therapeutic strategies.

Keywords: Breast cancer; CARM1; Cell migration; Cell proliferation; YIPF2

DOI: https://doi.org/10.1016/j.tranon.2026.103073

bioRxiv. 2026 Sep 28. pii: 2026.09.24.754142. [Epub ahead of print]

SOX4 Reprograms Adipose Stromal Cells into a Cancer-Associated Fibroblast- like State to Drive Metabolic Disease.

Karima Drareni, Ryan P Calhoun, Lan Cheng, Camille E M Piguet, Lin Liu, Sarah Traynor, Josephine M Tan, Marco Angelozzi, David M Merrick, Veronique Lefebvre, Patrick Seale.

Pathogenic adipose tissue remodeling promotes metabolic disease in obesity, but the mechanisms that establish this unhealthy tissue state remain poorly understood. Here, we show that obesity drives SOX4-dependent reprogramming of mesenchymal stromal cells (MSCs) into cancer-associated fibroblast-like (CAF-like) cells that promote adipose tissue dysfunction. TGFβ signaling is elevated in obesity and activates SOX4 in mouse and human MSCs, inducing their conversion to a CAF-like state. In mice, MSC-specific SOX4 activation induces the CAF-like program and exacerbates adipose tissue inflammation and glucose intolerance, whereas Sox4 deletion attenuates inflammation and improves glucose homeostasis during obesity. We further identify the growth factor Midkine (MDK) as a SOX4-regulated paracrine effector produced by CAF-like cells. MDK inhibition in obese mice reduces adipose tissue inflammation and improves metabolic function. Together, these findings define a TGFβ-SOX4-MDK stromal signaling axis that drives pathological adipose tissue remodeling in obesity and highlight this pathway as a potential therapeutic target for improving metabolic health.

DOI: https://doi.org/10.64898/2026.09.24.754142

Oncoimmunology. 2026 Dec 31. 15(1): 2746847

Estradiol-associated extracellular signaling in the human breast in vivo identifies mast cells as tumor-supportive stromal mediators.

Annelie Abrahamsson, Xingyue Wang, Wen Zhong, Charlotta Dabrosin.

Sex steroid exposure is a major risk factor for breast cancer initiation and progression through incompletely understood mechanisms. Novel therapeutics for prevention and treatment of estrogen-dependent breast cancer are needed. Cell-cell interactions within the microenvironment contribute to breast cancer progression through extracellular signaling. Here, extracellular proteins were sampled directly from live normal human breast tissue and breast cancers using microdialysis, and 1,101 proteins were quantified. Mechanistic studies were performed in cultured intact normal human breast tissue and mast cells. Findings were validated in vivo using ER+ breast cancer models in immunocompetent and immunocompromised mice and in a zebrafish xenograft model. We identified a breast tissue-specific extracellular protein signature comprising 150 proteins associated with local estradiol (E2) levels, of which several were linked to mast cell biology, including stem cell factor (SCF). Human ER+ breast tumors exhibited increased extracellular SCF levels and higher mast cell density, which was associated with poorer overall survival. In normal human breast tissue, E2 increased mast cell abundance and activity. In vitro, E2 rapidly activated mast cells, an effect blocked by desloratadine. In mouse breast cancer models, E2 increased and fulvestrant reduced mast cell density. In the zebrafish, mast cells promoted ER+ breast cancer growth, which was further enhanced by E2 and abrogated by desloratadine. Overall, our findings identify mast cells as estrogen-responsive stromal mediators and support targeting mast cell-dependent pathways as a potential strategy for the prevention and treatment of estrogen-dependent breast cancer.

Keywords: Microdialysis; innate immune cells; sex steroids; zebrafish

DOI: https://doi.org/10.1080/2162402X.2026.2746847

bioRxiv. 2026 Oct 01. pii: 2026.09.30.755755. [Epub ahead of print]

P4HA1 sustains endocrine resistance in luminal breast cancer via regulation of cellular stress.

Dalton Hironaka, Baorui Kang, Dongsung Kim, Haichang Li, Rachel Schiff, Ren Xu, Gaofeng Xiong.

The hormone receptor-positive luminal subtype accounts for approximately 70% of all diagnosed breast cancer cases, with endocrine regimens serving as the first-line therapy. However, 30% to 50% of luminal breast cancer patients acquire therapeutic resistance with five to ten years of treatment. Understanding the mechanisms of endocrine resistance and identifying new therapeutic targets remain urgent priorities. Here, we demonstrate that expression of the alpha subunit of prolyl 4-hydroxylase (P4HA1), a key collagen-modifying enzyme, is significantly upregulated in endocrine therapy-resistant luminal breast cancer cells compared to parental endocrine therapy-sensitive cells. Clinically, elevated P4HA1 expression correlates with shortened relapse-free survival in patients with luminal breast cancer. Genetically knocking down P4HA1 or pharmacologically inhibiting its activity successfully restores the sensitivity of endocrine-resistant luminal breast cancer cells to hormone therapy. Mechanistically, we reveal that combining P4HA1 inactivation with endocrine treatment dramatically enhances endoplasmic reticulum (ER) stress-related gene expression. Consistently, treating resistant cells with an exogenous ER stress inducer similarly enhances sensitivity to hormone therapy. Furthermore, we demonstrate that ER stress induced by P4HA1 inactivation is molecularly mediated by an accumulation of reactive oxygen species (ROS). Together, these findings uncover a novel, non-canonical role for P4HA1 as a critical mediator linking endocrine resistance to cellular stress adaptations, positioning P4HA1 as a promising therapeutic vulnerability in endocrine-resistant breast cancer. P4HA1 serves as a necessary role in maintenance resistant state, making it a viable target for combination therapies to overcome endocrine resistance.

DOI: https://doi.org/10.64898/2026.09.30.755755

J Clin Pract Res. 2026 Sep;48(5): 521-529

FOXM1 Drives Subtype-Specific Dysregulation of Prognostic miRNAs in Breast Cancer Cells.

Zuhal Hamurcu, Venhar Cınar, Ayse Doga Karipcin, Ahsen Güler, Zeynep Yılmaz Sükranlı, Mehmet Memis, Elif Funda Sener, Serpil Taheri, Bulent Ozpolat.

Objective: Breast cancer is a heterogeneous disease comprising distinct molecular subtypes, including estrogen receptor-positive (ER+) breast cancer and triple-negative breast cancer (TNBC). MicroRNAs (miRNAs) regulate post-transcriptional gene expression and play important roles in cancer progression by functioning as oncogenic or tumor-suppressive molecules. Forkhead box M1 (FOXM1) is an oncogenic transcription factor that is frequently upregulated in aggressive breast cancers, particularly TNBC, and is associated with proliferation, invasion, metastasis, therapy resistance, and poor prognosis.
Materials and Methods: Clinically relevant miRNAs associated with survival in patients with ER+ and ER- breast cancer were identified using publicly available datasets. The expression levels of miR-34a-5p, miR-873-5p, miR-193b-5p, miR-330-5p, miR-10b-5p, miR-155-5p, and miR-484 were evaluated in MDA-MB-231 TNBC cells and MCF-7 ER+ breast cancer cells following FOXM1 knockdown.
Results: FOXM1 knockdown was associated with increased expression of several tumor-suppressive miRNAs, including miR-34a-5p, miR-873-5p, miR-193b-5p, miR-330-5p, miR-10b-5p, and miR-484, in MDA-MB-231 cells. In contrast, most of these miRNAs were not markedly altered in MCF-7 cells, except for miR-10b-5p, whose expression decreased following FOXM1 knockdown. miR-155-5p expression remained largely unchanged in both cell lines.
Conclusion: Our findings demonstrate that FOXM1 knockdown was associated with differential expression of clinically relevant miRNAs in the two breast cancer cell models examined. These findings suggest that FOXM1-associated alterations in miRNA expression may contribute to the aggressive phenotype of TNBC and warrant further mechanistic investigation.

Keywords: Breast cancer; FOXM1; estrogen receptor-positive breast cancer; miR-10b-5p; miR-193b-5p; miR-34a-5p; microRNA; triple-negative breast cancer

DOI: https://doi.org/10.14744/cpr.2026.18248