bims-merabr 2025-04-20 papers

Int J Mol Sci. 2025 Mar 27. pii: 3083. [Epub ahead of print]26(7):

Unveiling Matrix Metalloproteinase 13's Dynamic Role in Breast Cancer: A Link to Physical Changes and Prognostic Modulation.

Xiaomeng Sun, Xiaojuan Hu.

The biomechanical properties of the extracellular matrix (ECM) including its stiffness, viscoelasticity, collagen architecture, and temperature constitute critical biomechanical cues governing breast cancer progression. Matrix metalloproteinase 13 (MMP13) is an important marker of breast cancer and plays important roles in matrix remodelling and cell metastasis. Emerging evidence highlights MMP13 as a dynamic modulator of the ECM's physical characteristics through dual mechanoregulatory mechanisms. While MMP13-mediated collagen degradation facilitates microenvironmental softening, thus promoting tumour cell invasion, paradoxically, its crosstalk with cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) drives pathological stromal stiffening via aberrant matrix deposition and crosslinking. This biomechanical duality is amplified through feedforward loops with an epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) populations, mediated by signalling axes such as TGF-β/Runx2. Intriguingly, MMP13 exhibits context-dependent mechanomodulatory effects, demonstrating anti-fibrotic activity and inhibiting the metastasis of breast cancer. At the same time, angiogenesis and increased metabolism are important mechanisms through which MMP13 promotes a temperature increase in breast cancer. Targeting the spatiotemporal regulation of MMP13's mechanobiological functions may offer novel therapeutic strategies for disrupting the tumour-stroma vicious cycle.

Keywords: MMP13; breast cancer; stiffness; structure; temperature

DOI: https://doi.org/10.3390/ijms26073083

bioRxiv. 2025 Mar 31. pii: 2025.03.28.645549. [Epub ahead of print]

Hypertrophic adipocytes increase extracellular vesicle-mediated lipid release and reprogram breast cancer cell metabolism.

Garrett F Beeghly, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.

Obesity worsens cancer-specific survival and all-cause mortality for women diagnosed with breast cancer. Rich in adipose tissue, the breast exhibits increased adipocyte size in obesity, which correlates with poor prognosis. However, adipocyte size is highly heterogeneous as adipose tissue expands through both hyperplasia and hypertrophy; and adipocyte size can increase independently of weight gain. Despite these observations, the impact of adipocyte size on breast cancer cell behavior remains unclear due to insufficient approaches to isolate adipocytes based on size and maintain them in culture for mechanistic studies. Here, we develop strategies to culture size-sorted adipocytes from two mouse models of obesity and test their functional impact on tumor cell malignancy. We find that large adipocytes are transcriptionally distinct from small adipocytes and are enriched for gene sets related to adipose tissue dysfunction, including altered lipid processing. In coculture studies, large adipocytes promote lipid accumulation in breast cancer cells, and enhance their migration, proliferation, and aerobic metabolism in a manner dependent on fatty acid oxidation. These changes coincide with increased release of extracellular vesicles by large versus small adipocytes, which transfer lipid to recipient tumor cells. Moving forward, our findings suggest that adipocyte size could serve as a prognostic biomarker for women with breast cancer and help identify new therapeutic targets to advance clinical outcomes for these patients.

DOI: https://doi.org/10.1101/2025.03.28.645549

Proc Natl Acad Sci U S A. 2025 Feb 25. 122(8): e2420383122

A circRNA-mRNA pairing mechanism regulates tumor growth and endocrine therapy resistance in ER-positive breast cancer.

Jia Yi, Jiao Du, Xue Chen, Rui-Chao Nie, Guo-Sheng Hu, Lei Wang, Yue-Ying Zhang, Shang Chen, Xiao-Sha Wen, Di-Xian Luo, Hua He, Wen Liu.

The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and drug resistance remain incompletely understood. Elevated expression of CCND1 is linked to enhanced invasiveness, poorer prognosis, and resistance to drug therapies in ER-positive breast cancer. In this study, we identify a highly expressed circular RNA (circRNA) derived from FOXK2, called circFOXK2, which plays a key role in stabilizing CCND1 mRNA, thereby promoting cell cycle progression, cell growth, and endocrine therapy resistance in ER-positive breast cancer cells. Mechanistically, circFOXK2 binds directly to CCND1 mRNA via RNA-RNA pairing and recruits the RNA-binding protein ELAVL1/HuR, stabilizing the CCND1 mRNA and enhancing CCND1 protein levels. This results in activation of the CCND1-CDK4/6-p-RB-E2F signaling axis, driving the transcription of downstream E2F target genes and facilitating the G1/S transition during cell cycle progression. Notably, targeting circFOXK2 with antisense oligonucleotide (ASO-circFOXK2) suppresses ER-positive breast cancer cell growth both in vitro and in vivo. Moreover, combination therapy with ASO-circFOXK2 and tamoxifen exhibits synergistic effects and restores tamoxifen sensitivity in tamoxifen-resistant cells. Clinically, high circFOXK2 expression is positively correlated with CCND1 levels in both ER-positive breast cancer cell lines and patient tumor tissues. Overall, our findings reveal the critical role of circFOXK2 in stabilizing the oncogene CCND1 and promoting cancer progression, positioning circFOXK2 as a potential therapeutic target for ER-positive breast cancer in clinical settings.

Keywords: CCND1; RNA-RNA pairing; breast cancer; circFOXK2; endocrine therapy resistance

DOI: https://doi.org/10.1073/pnas.2420383122

bioRxiv. 2025 Apr 02. pii: 2025.03.28.645920. [Epub ahead of print]

Substrate stiffness regulates triple-negative breast cancer signaling through CXCR4 receptor dynamics.

Kenneth K Y Ho, Johanna M Buschhaus, Anne Zhang, Alyssa C Cutter, Brock Humphries, Gary D Luker.

Biophysical properties of the extracellular matrix (ECM), such as mechanical stiffness, directly regulate behaviors of cancer cells linked to cancer initiation and progression. Cells sense and respond to ECM stiffness in the context of dynamic changes in biochemical inputs, such as growth factors and chemokines. While commonly studied as isolated inputs, mechanisms by which combined effects of mechanical stiffness and biochemical factors affect functions of cancer cells remain poorly defined. Using a combination of elastically supportive surface (ESS) culture dishes with defined stiffnesses and single-cell imaging, we report here that culturing cells on a stiff (28 kPa) versus soft (1.5 kPa) substrate increases CXCR4 and EGFR expression and promotes greater ligand-dependent internalization of CXCR4. In addition to increased CXCR4 expression, a stiff ECM also increases basal activation of Akt and ERK as well as signaling through these kinases in response to CXCL12-α and EGF and promotes migration of triple negative breast cancer (TNBC) cells. These data implicate receptor dynamics as a key mediator of Akt and ERK signaling as a mechanism for adverse effects of enhanced ECM stiffness on disease progression in TNBC.

DOI: https://doi.org/10.1101/2025.03.28.645920

Transl Cancer Res. 2025 Mar 30. 14(3): 1824-1835

Estrogen receptor β inhibits breast cancer migration and promotes its apoptosis through NF-κB/IL-8 signaling.

Yanke Sui, Zuge Liu, Yao Yao, Shuting Zhang, Yuxiang Wang, Yuanyuan Wang, Bin Kong.

Background: Estrogen receptor β (ERβ) has been confirmed to play a tumor suppressor effect in various cancers, but its role in breast cancer is still unclear, especially in triple-negative breast cancer. In this study, we aim to explore the expression of ERβ in breast cancer and its influence on the biological behavior of breast cancer cells, including its potential mechanisms of action.
Methods: MCF-7 and MDA-MB-231 breast cancer cell lines were transfected with ERβ-overexpressing lentivirus and treated with pyrrolidinedithiocarbamate ammonium, a specific inhibitor of NF-κB. Cell Counting Kit-8, colony formation, and apoptosis assays were used to examine breast cancer cells viability in vitro. We further investigated breast cancer cells mobility and migration through wound healing and transwell assays. Western blot and quantitative real-time polymerase chain reaction analysis determined the expression of related genes at the protein and messenger RNA levels.
Results: Breast cancer tissues displayed significantly lower ERβ messenger RNA and protein levels compared to adjacent healthy tissues. Conversely, interleukin-8 (IL-8) messenger RNA and protein levels were significantly higher in cancer tissues. ERβ overexpression led to a reduction in the expression of NF-κB pathway proteins like p-IκBα and p-P65, thereby inhibiting the pathway and consequently decreasing the expression of the inflammatory factor IL-8. This resulted in decreased mobility and migration of breast cancer cells, accompanied by increased apoptosis.
Conclusions: This study demonstrates that ERβ suppresses the NF-κB/IL-8 signaling axis by inhibiting the phosphorylation of IκBα and P65, consequently restricting breast cancer cell mobility and migration while promoting apoptosis.

Keywords: Estrogen receptor (ERβ); NF-κB; breast cancer; interleukin-8 (IL-8)

DOI: https://doi.org/10.21037/tcr-24-1267