Adipocyte Hsp47: A Novel Regulator of Obesity and Obesity-Associated Breast Cancer
Baorui Kang1, Ren Xu2, Gaofeng Xiong3*
1Department of Veterinary Biosciences, OSU Nutrition Program, The Ohio State University, Columbus, OH 43210, USA
2Markey Cancer Center, Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
3Department of Veterinary Biosciences, Comprehensive Cancer Center, The Ohio State University, 10.1002/hep.32181 From NLM Medline. Columbus, OH 43210, USA
Obesity or being overweight is a growing global health concern and a significant risk factor for various cancers, including breast cancer. The increased incidence and poor adverse outcomes of breast cancer in individuals with obesity have prompted research into the molecular mechanisms linking obesity, adipose tissue remodeling, and tumor progression. Adipose tissue, which surrounds mammary tumor, is viewed not only as an energy storage and endocrine organ, but also as an active participant in breast cancer biology. Fibrosis, a key feature of obese adipose tissue, can contribute to a pro-tumorigenic macroenvironment by altering extracellular matrix (ECM) deposition, composition and alignment. Heat Shock Protein 47 (Hsp47) is a chaperone protein facilitating collagen secretion. Recent studies indicate that elevated Hsp47 expression in adipocytes is associated with obesity, sheds new light on the mechanisms underlying obesity-associated breast cancer progression. Adipocyte-expressed Hsp47 promotes obesity-associated breast cancer progression by contributing to ECM deposition and modulating immune responses within the tissue environment. It reveals a novel role of adipose tissue in breast cancer progression and has identified Hsp47 as a potential therapeutic target for obesity-associated breast cancer.
DOI: 10.29245/2578-2967/2025/3.1211 View / Download PdfPharmacological Inhibition of cFLIP Targets Breast Cancer Stem Cells
Rhiannon French1, Olivia Hayward1, Andreia Ribeiro da Silva1, Timothy Robinson2, Gillian Seaton1 and Richard Clarkson1*
1European Cancer Stem Cell Research Institute, Cardiff University School of Biosciences, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
2Bristol Medical School (PHS), University of Bristol, Oakfield House, Oakfield Grove, Clifton, Bristol, BS8 2BN, UK
Therapeutic targeting of tumour initiating, cancer stem cells (CSCs), offers the potential to improve long-term responses to cancer treatments. The apoptosis related protein Cellular FLICE-Like Inhibitory Protein (cFLIP) has previously been reported to protect breast cancer cells and breast CSCs from the cytotoxic effects of chemotherapy and apoptosis-inducing agents.
We recently described the development of a small-molecule protein-protein inhibitor of cFLIP (OH14) that sensitizes refractory breast cancer cells to the death-receptor agonist Tumour Necrosis Factor Alpha Receptor Apoptosis Inducing Ligand (TRAIL).
Here we investigated whether the pharmacological inhibition of cFLIP also targeted breast CSCs.
Human breast cancer cell lines and primary-derived breast cancer samples were subjected to OH14 with or without TRAIL and assessed for bCSC viability by colony-formation and tumoursphere assay in vitro and xenograft tumour initiation in vivo. OH14 potentiated a reduction in the number of bCSCs after TRAIL treatment, mimicking the sensitizing effects previously observed with epigenetic silencing of cFLIP. Moreover, prolonged inhibition of cFLIP alone, either by shRNA knockdown or treatment with OH14, reduced the bCSC pool, an outcome that was independent of caspases.
These data provide proof-of-principle for the use of pharmacological inhibitors of cFLIP to target bCSCs and highlights for the first time both apoptosis-dependent and independent mechanisms for cFLIP-mediated regulation of the breast cancer stem cell pool.
DOI: 10.29245/2578-2967/2025/2.1210 View / Download Pdf