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We previously demonstrated that lapatinib resistance in triple-negative breast cancer (TNBC) cells is associated with AnxA6 upregulation and accumulation of cholesterol in late endosomes. Here, we investigated the fate of AnxA6 and cholesterol in lapatinib-resistant (LAP-R) cells and whether extracellular AnxA6 influences TNBC cell survival. We demonstrate that reduced expression of AnxA6 in LAP-R cells decreased the secretion of MCP-1\/CCL2, CCL8\/IL-8, DKK1, TSP-1, and OPN by antibody arrays. The secretion of exosomes was also markedly reduced in AnxA6-depleted LAP-R cells, while AnxA6 upregulation stimulated the release of MCP-1 and exosomes. Compared to the respective controls, exosome-associated AnxA6, Rab7, and cholesterol levels were increased in exosomes isolated from AnxA6-expressing LAP-R cells. Mechanistically, we demonstrated by co-immunoprecipitation, GST pulldown, and proximity ligation assays that AnxA6 interacts with SNAP23, a component of the membrane fusion machinery. Finally, blocking extracellular AnxA6 with neutralizing antibodies reduced the viability of AnxA6-low TNBC cells but had little effect on AnxA6-high cells. These findings suggest that extracellular AnxA6 is critical for the survival of highly proliferative AnxA6-low basal-like breast cancer cells and that AnxA6 influences TNBC progression by facilitating the secretion of pro-inflammatory cytokines and cholesterol-enriched exosomes.<\/jats:p>","DOI":"10.3390\/cells15111013","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T08:09:16Z","timestamp":1780301356000},"page":"1013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Annexin A6 Modulates the Secretion of Pro-Inflammatory Cytokines and Exosomes via Interaction with SNAP23 in Triple-Negative Breast Cancer Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Nobelle I.","family":"Sakwe","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga Y.","family":"Korolkova","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc B.","family":"Vuong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alayjha D.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perrin J.","family":"Black","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Destiny D.","family":"Ball","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonisha R.","family":"McIntosh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Portia L.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6005-775X","authenticated-orcid":false,"given":"Diva S.","family":"Whalen Melvin","sequence":"additional","affiliation":[{"name":"Department of Biology, Tougaloo College, Tougaloo, MS 39174, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4636-2889","authenticated-orcid":false,"given":"Heather K.","family":"Beasley","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7730-952X","authenticated-orcid":false,"suffix":"Jr.","given":"Antentor O.","family":"Hinton","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4551-5174","authenticated-orcid":false,"given":"Josiah","family":"Ochieng","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2283-794X","authenticated-orcid":false,"given":"Amos M.","family":"Sakwe","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Graduate Studies, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Korolkova, O.Y., Widatalla, S.E., Williams, S.D., Whalen, D.S., Beasley, H.K., Ochieng, J., Grewal, T., and Sakwe, A.M. 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