{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T08:37:06Z","timestamp":1776155826535,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T00:00:00Z","timestamp":1739750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. Army Medical Research and Materiel Command (USAMRMC)","award":["W81XWH-10-1-0046"],"award-info":[{"award-number":["W81XWH-10-1-0046"]}]},{"name":"U.S. Army Medical Research and Materiel Command (USAMRMC)","award":["BC990959"],"award-info":[{"award-number":["BC990959"]}]},{"name":"U.S. Army Medical Research and Materiel Command (USAMRMC)","award":["BC024258"],"award-info":[{"award-number":["BC024258"]}]},{"name":"U.S. Army Medical Research and Materiel Command (USAMRMC)","award":["BC053405"],"award-info":[{"award-number":["BC053405"]}]},{"name":"U.S. Army Medical Research and Materiel Command (USAMRMC)","award":["U54CA163069"],"award-info":[{"award-number":["U54CA163069"]}]},{"name":"Department of Defense Breast Cancer Research Program","award":["W81XWH-10-1-0046"],"award-info":[{"award-number":["W81XWH-10-1-0046"]}]},{"name":"Department of Defense Breast Cancer Research Program","award":["BC990959"],"award-info":[{"award-number":["BC990959"]}]},{"name":"Department of Defense Breast Cancer Research Program","award":["BC024258"],"award-info":[{"award-number":["BC024258"]}]},{"name":"Department of Defense Breast Cancer Research Program","award":["BC053405"],"award-info":[{"award-number":["BC053405"]}]},{"name":"Department of Defense Breast Cancer Research Program","award":["U54CA163069"],"award-info":[{"award-number":["U54CA163069"]}]},{"name":"NIH","award":["W81XWH-10-1-0046"],"award-info":[{"award-number":["W81XWH-10-1-0046"]}]},{"name":"NIH","award":["BC990959"],"award-info":[{"award-number":["BC990959"]}]},{"name":"NIH","award":["BC024258"],"award-info":[{"award-number":["BC024258"]}]},{"name":"NIH","award":["BC053405"],"award-info":[{"award-number":["BC053405"]}]},{"name":"NIH","award":["U54CA163069"],"award-info":[{"award-number":["U54CA163069"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mammary intraductal macrophages (foam cells) in humans are the most commonly encountered cells in spontaneous breast nipple discharge, nipple aspirate fluid, and ductal lavage, yet their origin remains unproven. These cells, in both humans and murine model systems, increase in pregnancy, pseudopregnancy, and other conditions like proliferative fibrocystic disease and intraductal neoplasia, ductal carcinoma in situ (DCIS), where there is intraductal ectasia and obstruction. Previous immunocytochemical studies with macrophage (CD68, lysozyme), epithelial (cytokeratin, estrogen receptor), and myoepithelial (smooth muscle actin, CALLA, maspin) markers have indicated that intraductal foam cells are of macrophage lineage. These foam cells engage in phagocytosis of both endogenous and exogenous substances present within the ducts and are not proliferative. Although it has been suggested that foam cells could derive from tissue-specific and niche-specific precursors or circulating monocytes, to date no experimental nor clinical studies have provided direct proof of their origin. In this study, we provide evidence in both human and murine bone marrow transplant studies that intraductal foam cells are bone marrow-derived. We first studied a registry of sex-mismatched bone marrow transplant recipients who later in life had undergone breast biopsies for either proliferative fibrocystic disease, DCIS, or gynecomastia, and studied these biopsies by XY chromosome fluorescence in situ hybridization (FISH) and informative microsatellite polymorphic markers. The intraductal foam cells were of bone marrow donor-origin. Then, in the experimental bone marrow transplant murine studies, donor marrow from female ROSA26 containing the lacZ reporter were transplanted into either irradiated female recipient transgenic mice carrying the highly penetrant MMTV-pymT or FVB\/N background mice, where induced pluripotent stem (iPS) cells derived from tail vein fibroblasts of FVB\/N-Tg(MMTV-PyVT)634Mul\/J mice were subsequently injected into their mammary fat pads. In all of the transplanted recipient mice, the intraductal foam cells expressed the \u03b2-galactosidase (lacZ) reporter and also co-expressed markers of myeloid\u2013macrophage lineage. The number of donor-derived intraductal foam cells increased in pseudopregnancy 5-fold and in intraductal neoplasia 10-fold. Although macrophages of different origins and lineages are undoubtedly present within both the murine and human breasts, those macrophages that qualify as phagocytic intraductal foam cells are bone marrow-derived.<\/jats:p>","DOI":"10.3390\/ijms26041699","type":"journal-article","created":{"date-parts":[[2025,2,17]],"date-time":"2025-02-17T03:41:47Z","timestamp":1739763707000},"page":"1699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Bone Marrow Origin of Mammary Phagocytic Intraductal Macrophages (Foam Cells)"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3760-4989","authenticated-orcid":false,"given":"Sanford H.","family":"Barsky","sequence":"first","affiliation":[{"name":"Department of Pathology, Anatomy and Cell Biology, The Clinical and Translational Research Center of Excellence, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krista","family":"Mcphail","sequence":"additional","affiliation":[{"name":"Star Diagnostics Laboratories, 215 E Warm Springs Rd., Ste 108, Las Vegas, NV 89119, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4734-4524","authenticated-orcid":false,"given":"Justin","family":"Wang","sequence":"additional","affiliation":[{"name":"Scripps Mercy Hospital, MER 35, San Diego, CA 92103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert M.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"AntiCancer, Inc., 7917 Ostow St., Suite B, San Diego, CA 92111, USA"},{"name":"Department of Surgery, University of California at San Diego, 9300 Campus Point Drive, #7220, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Pathology, Anatomy and Cell Biology, The Clinical and Translational Research Center of Excellence, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Boulevard, Nashville, TN 37208, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1093\/jnci\/93.23.1791","article-title":"Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid","volume":"93","author":"Wrensch","year":"2001","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/jnci\/59.4.1073","article-title":"Cytologic evaluation of breast fluid in the detection of breast disease","volume":"59","author":"Sartorius","year":"1977","journal-title":"J. Natl. 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