{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T06:08:02Z","timestamp":1774332482333,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T00:00:00Z","timestamp":1767484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(1) Cancer has been shown to contribute to the progression of atherosclerosis, while inflammatory aspects of atherosclerosis can exert profound effects on cancer development and outcomes. TA-MUC1 (Tumour-associated Mucin 1) is a transmembrane glycoprotein that is overexpressed in many human epithelial cancers lining the intestine. Interestingly, the lack of intestinal MUC1 has been shown to impair cholesterol uptake in MUC1\u2212\/\u2212 mice. (2) To investigate whether TA-MUC1 could have specific effects on cholesterol metabolism and, thereby, have the potential of impacting the pathogenesis of atherosclerosis in cancer patients. (3) The effect of TA-MUC1 on cholesterol and lipid metabolism was assayed using MUC1 gene knock down breast cancer cells. An in vitro coculturing model similar to in vivo biological conditions was used to determine that TA-MUC1 could also modulate the cholesterol metabolism of other cells. (4) Reduction or inhibition of TA-MUC1 activity resulted in a significant alteration in a number of the signalling pathways and proteins that are relevant to abnormal cholesterol metabolism (p &lt; 0.0001). Coculturing of TA-MUC1 cancer cells with THP-1 cells also notably effectively induced monocytic THP-1 cell differentiation towards foam cells\u2014foam cells being a characteristic feature of atherosclerotic blood vessels. (5) Previously, we found TA-MUC1 downregulation led to a reduction in procoagulant and prothrombotic properties of the cancer cells as well as modulation of the aberrant calcium signalling pathways of cancer cells. Taken together with these current results, this suggests that TA-MUC1 in cancer cells has multiple effects on cholesterol and lipid metabolism, which also impacts other cells in the cellular bioenvironment. TA-MUC1 could thereby act as an important pathogenic effector of atherosclerosis in cancer. These results can also be considered in respect of the therapeutic anti-MUC1 antibody, which was able to reduce the effect of TA-MUC1 on cholesterol metabolism. Modulation of cholesterol metabolism via targeting TA-MUC1 could, therefore, be of great benefit to cancer patients with atherosclerosis.<\/jats:p>","DOI":"10.3390\/ijms27010518","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T13:35:47Z","timestamp":1767620147000},"page":"518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tumour-Associated MUC1 Exerts Multiple Effects on Cholesterol and Lipid Metabolism\u2014A Potential Pathogenic Effector of Atherosclerosis in Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9341-5330","authenticated-orcid":false,"given":"Yunliang","family":"Chen","sequence":"first","affiliation":[{"name":"Thrombosis Research Institute, London SW3 6LR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Scully","sequence":"additional","affiliation":[{"name":"Thrombosis Research Institute, London SW3 6LR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.arcmed.2017.03.005","article-title":"Therosclerosis and Cancer; A Resemblance with Far-reaching Implications","volume":"48","year":"2017","journal-title":"Arch. Med. Res."},{"key":"ref_2","first-page":"487","article-title":"The Two-way Relationship Between Cancer and Atherosclerosis","volume":"72","author":"Cordero","year":"2019","journal-title":"Rev. Espa\u00f1ola Cardiol. (Engl. Ed.)"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Diao, Y., Liu, Z., Chen, L., Zhang, W., and Sun, D. (2022). The Relationship Between Cancer and Functional and Structural Markers of Subclinical Atherosclerosis: A Systematic Review and Meta-Analysis. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.849538"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"ehae666.3153","DOI":"10.1093\/eurheartj\/ehae666.3153","article-title":"Increased prevalence of coronary atherosclerosis in cancer survivors: A matched cross-sectional study with coronary CT angiography","volume":"45","author":"Polomski","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100123","DOI":"10.1016\/j.tru.2022.100123","article-title":"Tumour-associated Mucin1 correlates with the procoagulant properties of cancer cells of epithelial origin","volume":"9","author":"Chen","year":"2022","journal-title":"Thromb. Update"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chen, Y., and Scully, M. (2023). Downregulation of Mucin1 in Cancer Cells is Associated with Modulation of Calcium signalling Pathways and Alteration in Procoagulant Related Activity. Med. Res. Arch., 11.","DOI":"10.18103\/mra.v11i6.3890"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Aguilar-Ballester, M., Herrero-Cervera, A., Vinu\u00e9, \u00c1., Mart\u00ednez-Herv\u00e1s, S., and Gonz\u00e1lez-Navarro, H. (2020). Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis. Nutrients, 12.","DOI":"10.3390\/nu12072021"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Katsi, V., Papakonstantinou, I., and Tsioufis, K. (2023). Atherosclerosis, Diabetes Mellitus, and Cancer: Common. Epidemiology, Shared Mechanisms, and Future Management. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411786"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101043","DOI":"10.1016\/j.tranon.2021.101043","article-title":"Influence of cholesterol on cancer progression and therapy","volume":"14","author":"Mayengbam","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13045-023-01498-2","article-title":"Lipid metabolic reprogramming in tumor microenvironment: From mechanisms to therapeutics","volume":"16","author":"Jin","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12944-024-02426-0","article-title":"Targeting lipid metabolism: Novel insights and therapeutic advances in pancreatic cancer treatment","volume":"24","author":"Zhang","year":"2025","journal-title":"Lipids Health Dis."},{"key":"ref_12","first-page":"126","article-title":"MUC1: A Novel Metabolic Master Regulator","volume":"1845","author":"Mehla","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5837","DOI":"10.1073\/pnas.0812029106","article-title":"MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment","volume":"106","author":"Pitroda","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"G547","DOI":"10.1152\/ajpgi.00097.2004","article-title":"Lack of the intestinal Muc1 mucin impairs cholesterol uptake and absorption but not fatty acid uptake in Muc1\u2212\/\u2212 mice","volume":"287","author":"Wang","year":"2004","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.it.2019.10.002","article-title":"Foam Cells: One Size Doesn\u2019t Fit All","volume":"40","author":"Guerrini","year":"2019","journal-title":"Trends Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gui, Y., Zheng, H., and Cao, R.Y. (2022). Foam Cells in Atherosclerosis: Novel insights into its origins, consequences, and molecular mechanisms. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.845942"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ijaz, A., Yarlagadda, B., and Orecchioni, M. (2025). Foamy macrophages in atherosclerosis: Unraveling the balance between pro- and anti-inflammatory roles in disease progression. Front. Cardiovasc. Med., 12.","DOI":"10.3389\/fcvm.2025.1589629"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.vph.2018.08.002","article-title":"Foam cell formation: A new target for fighting atherosclerosis and cardiovascular disease","volume":"112","author":"Maguire","year":"2019","journal-title":"Vasc. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1080\/14728222.2023.2288272","article-title":"Lipid-laden foam cells in the pathology of atherosclerosis: Shedding light on new therapeutic targets","volume":"27","author":"Galindo","year":"2023","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29116","DOI":"10.1074\/jbc.M202867200","article-title":"Potent modification of low-density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation","volume":"277","author":"Hanasaki","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S419","DOI":"10.1016\/S0002-8703(99)70266-8","article-title":"Atherosclerosis is an inflammatory disease","volume":"138","author":"Ross","year":"1999","journal-title":"Am. Heart J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1161\/01.ATV.16.7.831","article-title":"The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994","volume":"16","author":"Navab","year":"1996","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Phuangbubpha, P., Thara, S., Sriboonaied, P., Saetan, P., Tumnoi, W., and Charoenpanich, A. (2023). Optimizing THP-1 Macrophage Culture for an Immune-Responsive Human Intestinal Model. Cells, 12.","DOI":"10.3390\/cells12101427"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s10911-024-09556-2","article-title":"Protocols for Co-Culture Phenotypic Assays with Breast Cancer Cells and THP-1-Derived Macrophages","volume":"29","author":"Mazan","year":"2024","journal-title":"J. Mammary Gland. Biol. Neoplasia"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Vis, M.A.M., Ito, K., and Hofmann, S. (2020). Impact of Culture Medium on Cellular Interactions in in vitro Co-culture Systems. Front. Bioeng. Biotechnol., 8.","DOI":"10.3389\/fbioe.2020.00911"},{"key":"ref_26","first-page":"27","article-title":"Lipid metabolism in cancer progression and therapeutic strategies","volume":"2","author":"Fu","year":"2020","journal-title":"Med. Comm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/onc.2012.158","article-title":"MUC1-C oncoprotein as a target in breast cancer: Activation of signaling pathways and therapeutic approaches","volume":"32","author":"Kufe","year":"2013","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1158\/1078-0432.CCR-14-3000","article-title":"Intracellular Targeting of the Oncogenic MUC1-C Protein with a Novel GO-203 Nanoparticle Formulation","volume":"21","author":"Hasegawa","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12943-017-0608-9","article-title":"Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer","volume":"16","author":"Ahmad","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Heublein, S., Page, S., Mayr, D., Schmoeckel, E., Trillsch, F., Marm\u00e9, F., Mahner, S., Jeschke, U., and Vattai, A. (2019). Potential interplay of the Gatipotuzumab epitope TA-MUC1 and estrogen receptors in ovarian cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020295"},{"key":"ref_31","first-page":"1010428318797880","article-title":"Colon cancer-derived conditioned medium induces differentiation of THP-1 monocytes into a mixed population of M1\/M2 cells","volume":"40","author":"Dudek","year":"2018","journal-title":"Tumor Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0022-2275(20)42241-2","article-title":"THP-1 cells form foam cells in response to coculture with lipoproteins but not platelets","volume":"32","author":"Banka","year":"1991","journal-title":"J. Lipid Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/cr.2017.8","article-title":"Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis","volume":"27","author":"Luo","year":"2017","journal-title":"Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1161\/01.ATV.20.8.1961","article-title":"Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57Bl\/6 mice","volume":"20","author":"Herijgers","year":"2000","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1161\/01.CIR.103.8.1142","article-title":"Evidence of macrophage foam cell formation by very low-density lipoprotein receptor: Interferon-gamma inhibition of very low-density lipoprotein receptor expression and foam cell formation in macrophages","volume":"27","author":"Kosaka","year":"2001","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1002\/cac2.12495","article-title":"CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway","volume":"43","author":"Chen","year":"2023","journal-title":"Cancer Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.biochi.2018.06.001","article-title":"Inflammation-induced mTORC2-Akt-mTORC1 signaling promotes macrophage foam cell formation","volume":"151","author":"Banerjee","year":"2018","journal-title":"Biochimie"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"303","DOI":"10.4330\/wjc.v12.i7.303","article-title":"MicroRNA sequences modulating inflammation and lipid accumulation in macrophage \u201cfoam\u201d cells: Implications for atherosclerosis","volume":"12","author":"Lightbody","year":"2020","journal-title":"World J. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1093\/cvr\/cvn156","article-title":"Role of microRNAs in vascular diseases, inflammation, and angiogenesis","volume":"79","author":"Urbich","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Kerneur, C., Cano, C.E., and Olive, D. (2022). Major pathways involved in macrophage polarization in cancer. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1026954"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.molmed.2014.02.007","article-title":"MUC1: A multifaceted oncoprotein with a key role in cancer progression","volume":"20","author":"Nath","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/rth2.12080","article-title":"The coagulation system in atherothrombosis: Implications for new therapeutic strategies","volume":"2","author":"Olie","year":"2018","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hill, C.N., Hern\u00e1ndez-C\u00e1ceres, M.P., Asencio, C., Torres, B., Solis, B., and Owen, G.I. (2020). Deciphering the Role of the Coagulation Cascade and Autophagy in Cancer-Related Thrombosis and Metastasis. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.605314"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12959-019-0194-8","article-title":"Protease-activated receptors (PARs): Mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases","volume":"17","author":"Heuberger","year":"2019","journal-title":"Thromb. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"103","DOI":"10.2174\/1573406411666150928111446","article-title":"Mechanisms in Atherosclerosis: The Role of Calcium","volume":"12","author":"Kalampogias","year":"2016","journal-title":"Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Neels, J.G., Leftheriotis, G., and Chinetti, G. (2023). Atherosclerosis Calcification: Focus on Lipoproteins. Metabolites, 13.","DOI":"10.3390\/metabo13030457"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1016\/0735-1097(94)90657-2","article-title":"Characterization of the relative thrombogenicity of atherosclerotic plaque components: Implications for consequences of plaque rupture","volume":"23","author":"Badimon","year":"1994","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Lee-Rueckert, M., Lappalainen, J., Kovanen, P.T., and Escola-Gil, J.C. (2022). Lipid-Laden Macrophages and Inflammation in Atherosclerosis and Cancer: An Integrative View. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.777822"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e004584","DOI":"10.1136\/jitc-2022-004584","article-title":"Lipid-loaded macrophages as new therapeutic target in cancer","volume":"10","author":"Marelli","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Poznyak, A.V., Nikiforov, N.G., Starodubova, A.V., Popkova, T.V., and Orekhov, A.N. (2021). Macrophages and foam cells: Brief overview of their role, linkage, and targeting potential in atherosclerosis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091221"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41569-019-0227-9","article-title":"Vascular smooth muscle cells in atherosclerosis","volume":"16","author":"Clarke","year":"2019","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.jconrel.2021.05.041","article-title":"Pitfalls and opportunities in quantitative fluorescence-based nanomedicine studies\u2014A commentary","volume":"335","author":"Simonsen","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/B978-0-12-386487-1.00017-1","article-title":"Analysis of cholesterol trafficking with fluorescent probes","volume":"108","author":"Maxfield","year":"2012","journal-title":"Methods Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1582237","DOI":"10.1080\/20013078.2019.1582237","article-title":"Pitfalls associated with lipophilic fluorophore staining of extracellular vesicles for uptake studies","volume":"8","author":"Simonsen","year":"2019","journal-title":"J. Extracell. Vesicles"},{"key":"ref_55","first-page":"10","article-title":"Uptake of Fluorescent Labeled Small Extracellular Vesicles In Vitro and in Spinal Cord","volume":"171","author":"Gupta","year":"2021","journal-title":"J. Vis. Exp."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1160\/TH12-12-0935","article-title":"Perturbation of the heparin\/heparin-sulfate interactome of human breast cancer cells modulates pro-tumourigenic effects associated with PI3K\/Akt and MAPK\/ERK signalling","volume":"109","author":"Chen","year":"2013","journal-title":"Thromb. Haemost."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1042\/BST20170400","article-title":"Latest developments in MUC1 immunotherapy","volume":"46","author":"Burchell","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/s41419-022-05345-z","article-title":"The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization","volume":"13","author":"Li","year":"2022","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T13:37:30Z","timestamp":1767620250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,4]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010518"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010518","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,4]]}}}