bims-merabr 2025-07-13 papers

BMC Cancer. 2025 Jul 09. 25(1): 1089

Plasma exosomes in insulin resistant obesity exacerbate progression of triple negative breast cancer.

Pablo Llévenes, Andrew Chen, Matthew Lawton, Alejandro N Rondón-Ortiz, Yuhan Qiu, Michael Seen, Stefano Monti, Gerald V Denis.

Breast cancer, the most common cancer among women worldwide, continues to pose significant public health challenges. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat due to the absence of receptors for estrogen, progesterone, or human epidermal growth factor receptor 2, rendering TNBC refractory to conventional targeted therapies. Emerging research underscores the exacerbating role of metabolic disorders, such as type 2 diabetes and obesity, on TNBC aggressiveness. Here, we investigate the critical cellular and molecular factors underlying this link. We explore the pivotal role of circulating plasma exosomes in modulating the tumor microenvironment and enhancing TNBC aggressiveness. We find that plasma exosomes from diet-induced obesity mice induce epithelial-mesenchymal transition features in TNBC cells, leading to increased migration in vitro and enhanced metastasis in vivo. We build on our previous reports demonstrating that plasma exosomes from obese, diabetic patients, and exosomes from insulin-resistant 3T3-L1 adipocytes, upregulate key transcriptional signatures of epithelial-mesenchymal transition in breast cancer. Bioinformatic analysis reveals that TNBC cells exhibit higher expression and activation of proteins related to the Rho-GTPase cascade, particularly the small Ras-related protein Rac1. Our approach suggests novel therapeutic targets and exosomal biomarkers, ultimately to improve prognosis for TNBC patients with co-morbid metabolic disorders.

Keywords: Breast cancer; Breast cancer migration; Exosome; Metastasis; Triple-negative

DOI: https://doi.org/10.1186/s12885-025-14447-8

Mol Carcinog. 2025 Jul 09.

Overexpression of Aquaporin-1 Promotes Epithelial-Mesenchymal Transition and Cancer Stem Cell Properties via Wnt/β-Catenin Signaling Pathway in Advanced Breast Cancer Cells.

Shan Wu, Haiyan Hu, Xiuhong Wang, Zhan Hua, Jianjun Zhou.

Tumor metastasis and the persistence of cancer stem cells (CSCs) are the main factors contributing to tumor malignancy, particularly in breast cancer. Uncovering the critical molecular mechanisms and therapeutic targets is essential for addressing this challenge. The present study revealed that aquaporin-1 (AQP1) was highly expressed in breast cancer and was closely associated with poor patient prognosis. AQP1 overexpression significantly enhanced multiple cellular processes in breast cancer cells, including cell proliferation, migration, invasion, spheroid formation, and three-dimensional (3D) spheroid invasion. Moreover, AQP1 activated the Wnt/β-catenin signaling pathway, and promoted the expression of epithelial-mesenchymal transition (EMT)-related markers (N-cadherin and vimentin) and CSC markers (SOX2 and c-Myc). Furthermore, small hairpin (sh)RNA-mediated downregulation of β-catenin confirmed the mechanism by which AQP1 promoted EMT and CSC properties through the activation of the Wnt/β-catenin signaling pathway. In conclusion, the present study elucidated the molecular mechanism through which AQP1 advanced breast cancer progression via the Wnt/β-catenin signaling pathway, providing insights into the mechanisms underlying breast cancer progression and offering valuable implications for developing novel therapeutic strategies.

Keywords: EMT; aquaporin‐1; breast cancer; cancer stem cells; β‐catenin

DOI: https://doi.org/10.1002/mc.70009

Breast Cancer Res. 2025 Jul 06. 27(1): 125

Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue.

Gaofeng Xiong, Daheng He, Dana Napier, Jing Chen, Haizhu Shi, Chun Li, Paula J Hurley, Chi Wang, Haining Zhu, Changcheng Zhou, Theresa J Bocklage, Ren Xu.

Fibrosis is an important feature of adipose tissue in obese individuals; nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.

DOI: https://doi.org/10.1186/s13058-025-02076-9

Med Oncol. 2025 Jul 07. 42(8): 313

Lovastatin inhibits adipocyte-associated increased proliferation, EMT and aggressiveness of breast cancer cells.

V K Soonu, M Diviya Lakshmanan, K N Naresh, K Sreejith.

Breast cancer is a significant health concern globally, with obesity exacerbating its prognosis. Despite advancements in therapies, challenges like chemoresistance and metastasis persist, especially in obese patients. Adipokines, upregulated in obese individuals, contribute to breast cancer progression by disrupting multiple signalling pathways. Lovastatin has shown potential as an adjuvant therapy due to its anti-tumour properties. In this study, we aimed to uncover the role of lovastatin in obesity-associated breast cancer. MCF-7 and MDA-MB-231 breast cancer cell lines, along with pre-adipocyte 3T3-L1 cells, were cultured and differentiated into mature adipocytes. Adipocyte-conditioned medium (ACM) was generated and used to culture the breast cancer cells. The effects of lovastatin combined with paclitaxel on cell viability, migration, and cell cycle were evaluated using MTT assay, scratch wound healing assay, and flow cytometry, respectively. Reverse docking was employed to identify potential lovastatin targets. Differentiated 3T3-L1 adipocytes successfully produced ACM, which significantly stimulated proliferation in both MCF-7 and MDA-MB-231 cells. Lovastatin, combined with paclitaxel, notably inhibited cell proliferation and migration, and induced cell cycle arrest in the S phase. Reverse docking identified key pathways and targets affected by lovastatin, including PPAR signalling. The study demonstrated that ACM from differentiated adipocytes enhances breast cancer cell proliferation and migration. Lovastatin effectively inhibits tumourigenic effect of ACM, suggesting its potential as a therapeutic agent for obesity-associated breast cancer via PPAR signalling. Further studies are warranted to validate these results and explore clinical applications.

Keywords: Adipocyte; Breast cancer; Lovastatin; Reverse docking

DOI: https://doi.org/10.1007/s12032-025-02874-3

Cancer Metab. 2025 Jul 10. 13(1): 35

Fatty acid synthase-derived lipid stores support breast cancer metastasis.

Chaylen Andolino, Eylem Kulkoyluoglu Cotul, Zilin Xianyu, Yun Li, Divya Bhat, Mitchell Ayers, Kimberly K Buhman, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.

Lipid accumulation is associated with breast cancer metastasis. However, the mechanisms underlying how breast cancer cells increase lipid stores and their functional role in disease progression remain incompletely understood. Herein we quantified changes in lipid metabolism and characterized cytoplasmic lipid droplets in metastatic versus non-metastatic breast cancer cells. 14C-labeled palmitate was used to determine differences in fatty acid (FA) uptake and oxidation. Despite similar levels of palmitate uptake, metastatic cells increase lipid accumulation and oxidation of endogenous FAs compared to non-metastatic cells. Isotope tracing also demonstrated that metastatic cells support increased de novo lipogenesis by converting higher levels of glutamine and glucose into the FA precursor, citrate. Consistent with this, metastatic cells displayed increased levels of fatty acid synthase (FASN) and de novo lipogenesis. Genetic depletion or pharmacologic inhibition of FASN reduced cell migration, survival in anoikis assays, and in vivo metastasis. Finally, global proteomic analysis indicated that proteins involved in proteasome function, mitotic cell cycle, and intracellular protein transport were reduced following FASN inhibition of metastatic cells. Overall, these studies demonstrate that breast cancer metastases accumulate FAs by increasingde novo lipogenesis, storing TAG as cytoplasmic lipid droplets, and catabolizing these stores to drive several FAO-dependent steps in metastasis.

Keywords: Breast cancer; FASN; Fatty acid synthase; Fatty acids; Lipid droplet; Lipid metabolism; Lipid storage; Mass spectrometry; Metastasis; TNBC

DOI: https://doi.org/10.1186/s40170-025-00404-3