{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:05:54Z","timestamp":1758672354993,"version":"3.44.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000001","name":"Alberta Cancer Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The role of prolactin (PRL) in breast cancer and its role within the context of the tumor microenvironment are not well understood. In our previous study, we demonstrated a cross-talk between the ataxia telangiectasia-mutated (ATM) DNA damage response pathway and the PRL-Janus-kinase-2 (JAK2)-signal transducer and activator of transcription-5 (STAT5)-heat shock protein-90 (HSP90) pathway. Here we investigated the role of PRL in tumor initiation and the effect of DNA damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used an <jats:italic>in vivo<\/jats:italic> model to assess the ability of breast cancer cells to initiate orthotopic xenograft tumor formation after DNA damage. Breast cancer cells engineered to secrete human PRL were treated with the DNA damaging agent doxorubicin and injected into the mammary fat pad of immune-deficient severe combined immunodeficiency disease (SCID) mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Doxorubicin and PRL combination increased the tumor latency, although PRL secretion alone did not change the tumor latency compared to the controls. Depletion of glycolipid asialo ganglioside-GM1-positive immune cells using anti-asialo GM1 antibody resulted in faster tumor formation only in the PRL-secreting breast cancer cells that were pre-treated with doxorubicin. Additionally, doxorubicin plus the PRL treatment of breast cancer cells was shown <jats:italic>in vitro<\/jats:italic> to attract cytotoxic NK cells compared to the controls, and this was dependent on the PRLR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These results demonstrate that combined breast cancer cell DNA damage and PRL exposure results in the anti-tumor cell activity of asialo-GM1-positive immune cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1586062","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T04:13:43Z","timestamp":1758600823000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Prolactin and DNA damage trigger an anti-breast cancer cell immune response"],"prefix":"10.3389","volume":"16","author":[{"given":"\u00d6d\u00fcl","family":"Karayazi Atici","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayantara","family":"Govindrajan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isbel","family":"Lopetegui-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constance A. M.","family":"Finney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carrie S.","family":"Shemanko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-16-0150","article-title":"Prolactin receptor in breast cancer: marker for metastatic risk","volume":"57","author":"Shemanko","year":"2016","journal-title":"J Mol Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.23.6926","article-title":"Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene","volume":"16","author":"Horseman","year":"1997","journal-title":"EMBO J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s10911-008-9073-9","article-title":"Transgenic models to study actions of prolactin in mammary neoplasia","volume":"13","author":"Arendt","year":"2008","journal-title":"J mammary gland Biol neoplasia"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djv338","article-title":"The role of prolactin in bone metastasis and breast cancer cell-mediated osteoclast differentiation","volume":"108","author":"Sutherland","year":"2016","journal-title":"J Natl Cancer Institute"},{"key":"B5","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.canlet.2015.06.010","article-title":"Anti-metastatic outcome of isoform-specific prolactin receptor targeting in breast cancer","volume":"366","author":"Yonezawa","year":"2015","journal-title":"Cancer letters"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-17-6-639","article-title":"Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects","volume":"17","author":"Ben-Jonathan","year":"1996","journal-title":"Endocr Rev"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1101\/gad.204636.112","article-title":"Autocrine prolactin: an emerging market for homegrown (prolactin) despite the imports","volume":"26","author":"Muthuswamy","year":"2012","journal-title":"Genes Dev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"R11","DOI":"10.1186\/bcr2819bcr2819","article-title":"Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer","volume":"13","author":"Arendt","year":"2011","journal-title":"Breast Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1023\/A:1023956223037","article-title":"Prolactin overexpression by MDA-MB-435 human breast cancer cells accelerates tumor growth","volume":"79","author":"Liby","year":"2003","journal-title":"Breast Cancer Res Treat"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206619","article-title":"Prolactin induces ERalpha-positive and ERalpha-negative mammary cancer in transgenic mice","volume":"22","author":"Rose-Hellekant","year":"2003","journal-title":"Oncogene"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc8145","article-title":"NSG-Pro mouse model for uncovering resistance mechanisms and unique vulnerabilities in human luminal breast cancers","volume":"7","author":"Sun","year":"2021","journal-title":"Sci Adv"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119820","article-title":"Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice","volume":"100","author":"Wennbo","year":"1997","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-18-0523","article-title":"Prolactin modulates TNBC aggresive phenotype limiting tumorigenesis endocrine-related cancer","volume":"26","author":"Lopez-Ozuna","year":"2019","journal-title":"Endocr Relat Cancer"},{"key":"B14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41523-021-00243-7","article-title":"The human intermediate prolactin receptor is a mammary proto-oncogene","volume":"7","author":"Grible","year":"2021","journal-title":"NPJ Breast Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00652","article-title":"ATM is required for the prolactin-induced HSP90-mediated increase in cellular viability and clonogenic growth after DNA damage","volume":"159","author":"Karayazi Atici","year":"2018","journal-title":"Endocrinology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"R91","DOI":"10.1677\/ERC-09-0253","article-title":"Novel roles of prolactin and estrogens in breast cancer: resistance to chemotherapy","volume":"17","author":"LaPensee","year":"2010","journal-title":"Endocrine-related cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/s0753-3322(05)80082-4","article-title":"Natural killer cells in breast cancer cell growth and metastasis in SCID mice","author":"Dewan","year":"2005","journal-title":"BioMed Pharmacother"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.134.6.3798","article-title":"Natural Killer (NK) cells are present in mice with severe combined immunodeficiency (scid)","volume":"134","author":"Dorshkind","year":"1985","journal-title":"J Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/291334a0","article-title":"In vivo effect of anti-asialo GM1 antibody on natural killer activity","volume":"291","author":"Kasai","year":"1981","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s11626-012-9522-z","article-title":"The bone morphogenetic protein receptor-1A pathway is required for lactogenic differentiation of mammary epithelial cells in vitro","volume":"48","author":"Perotti","year":"2012","journal-title":"In Vitro Cell Dev Biol Anim"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2005.06.003","article-title":"Quantitative assay of senescence-associated beta-galactosidase activity in mammalian cell extracts","volume":"343","author":"Gary","year":"2005","journal-title":"Anal Biochem"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e0141074","DOI":"10.1371\/journal.pone.0141074","article-title":"A novel method for assessment of natural killer cell cytotoxicity using image cytometry","volume":"10","author":"Somanchi","year":"2015","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","first-page":"C9","DOI":"10.1530\/ERC-16-0397","article-title":"Modeling estrogen receptor-positive breast cancers in mice: is it the best we can do","volume":"23","author":"Chatzistamou","year":"2016","journal-title":"Endocrine-related Cancer"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygcen.2011.11.014","article-title":"Methods for long-term 17beta-estradiol administration to mice","volume":"175","author":"Ingberg","year":"2012","journal-title":"Gen Comp Endocrinol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2015.42","article-title":"The breast tumor microenvironment alters the phenotype and function of natural killer cells","volume":"13","author":"Krneta","year":"2016","journal-title":"Cell Mol Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8851986","article-title":"Reevaluation of NOD\/SCID mice as NK cell-deficient models","volume":"2021","author":"Miao","year":"2021","journal-title":"BioMed Res Int"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bmt.1702702","article-title":"Natural killer cell depletion by anti-asialo GM1 antiserum treatment enhances human hematopoietic stem cell engraftment in NOD\/Shi-scid mice","volume":"26","author":"Yoshino","year":"2000","journal-title":"Bone Marrow Transplant"},{"key":"B28","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/jlb.37.5.597","article-title":"Reactivity of anti-asialo GM1 serum with tumouricidal and non-tumouricidal mouse macrophages","volume":"37","author":"Wiltrout","year":"1985","journal-title":"J leukocyte Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095951","article-title":"Regulation of ligands for the NKG2D activating receptor","volume":"31","author":"Raulet","year":"2013","journal-title":"Annu Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nri2604","article-title":"Oncogenic stress sensed by the immune system: role of natural killer cell receptors","volume":"9","author":"Raulet","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400271","article-title":"Reactive oxygen species- and DNA damage response-dependent NK cell activating ligand upregulation occurs at transcriptional levels and requires the transcriptional factor E2F1","volume":"193","author":"Soriani","year":"2014","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.140946","article-title":"CD45: a critical regulator of signaling thresholds in immune cells","volume":"21","author":"Hermiston","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01869","article-title":"Natural killer cells: development, maturation, and clinical utilization","volume":"9","author":"Abel","year":"2018","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01530-0","article-title":"Lactation-associated macrophages exist in murine mammary tissue and human milk","volume":"24","author":"Cansever","year":"2023","journal-title":"Nat Immunol"},{"key":"B35","article-title":"Major histocompatibility complex: Antigen processing and presentation","volume-title":"Autoimmunity: from bench to bedside","author":"Cruz-Tapias","year":"2013"},{"key":"B36","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/cdd.2013.26","article-title":"Molecular mechanisms of natural killer cell activation in response to cellular stress","volume":"21","author":"Chan","year":"2014","journal-title":"Cell Death differentiation"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-173914","article-title":"ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype","volume":"113","author":"Soriani","year":"2009","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030788","article-title":"Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule","volume":"198","author":"Bottino","year":"2003","journal-title":"J Exp Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.biochi.2023.09.021","article-title":"DNA damage-induced senescence is associated with metabolomic reprogramming in breast cancer cells","volume":"216","author":"George","year":"2024","journal-title":"Biochimie"},{"key":"B40","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/sj.cr.7290204","article-title":"Expression of prolactin receptor and response to prolactin stimulation of human NK cells","volume":"14","author":"Sun","year":"2004","journal-title":"Cell Research"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2021.101195","article-title":"Prolactin enhances T regulatory cell promotion of breast cancer through the long form prolactin receptor","volume":"14","author":"Chen","year":"2021","journal-title":"Transl Oncol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2010.04.012","article-title":"IL-10 alters prolactin receptor activity emulating that during breast cancer","volume":"51","author":"Paul","year":"2010","journal-title":"Cytokine"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-0030","article-title":"Natural killer cell regulation of breast cancer stem cells mediates metastatic dormancy","volume":"84","author":"Bushnell","year":"2024","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03614-z","article-title":"Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy","volume":"594","author":"Correia","year":"2021","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701830","article-title":"20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years","volume":"377","author":"Pan","year":"2017","journal-title":"N Engl J Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e0252662","DOI":"10.1371\/journal.pone.0252662","article-title":"MICA-G129R: A bifunctional fusion protein increases PRLR-positive breast cancer cell death in co-culture with natural killer cells","volume":"16","author":"Ding","year":"2021","journal-title":"PloS One"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100370","article-title":"NK cell-depleting anti-asialo GM1 antibody exhibits a lethal off-target effect on basophils in vivo","volume":"186","author":"Nishikado","year":"2011","journal-title":"J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2004.23.549","article-title":"Antitumor activity of eosinophils activated by IL-5 and eotaxin against hepatocellular carcinoma","volume":"23","author":"Kataoka","year":"2004","journal-title":"DNA and Cell Biology"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.4.2009","article-title":"NK markers are expressed on a high percentage of virus-specific CD8+ and CD4+ T cells","volume":"164","author":"Slifka","year":"2000","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8082","article-title":"Asialo GM1(+) CD8(+) T cells play a critical role in costimulation blockade-resistant allograft rejection","volume":"104","author":"Trambley","year":"1999","journal-title":"J Clin Invest"},{"key":"B51","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1385\/IR:36:1:13","article-title":"Antitumor activity of NK cells","author":"Yang","year":"2006","journal-title":"Immunologic Res"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/0091-6749(94)90336-0","article-title":"The eosinophil-mediated antitumor activity of interleukin-4","volume":"94","author":"Tepper","year":"1994","journal-title":"J Allergy Clin Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1158\/0008-5472.CAN-16-0993","article-title":"Basophils promote tumor rejection via chemotaxis and infiltration of CD8+ T cells","volume":"77","author":"Sektioglu","year":"2017","journal-title":"Cancer Res"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15751","article-title":"Involvement of protumor macrophages in breast cancer progression and characterization of macrophage phenotypes","volume":"114","author":"Komohara","year":"2023","journal-title":"Cancer Sci"},{"key":"B55","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s10911-016-9369-0","article-title":"Role of prolactin in promotion of immune cell migration into the mammary gland","volume":"22","author":"Dill","year":"2017","journal-title":"J mammary gland Biol neoplasia"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.4.1523","article-title":"Prolactin: structure, function, and regulation of secretion","volume":"80","author":"Freeman","year":"2000","journal-title":"Physiol Rev"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1159\/000067179","article-title":"Recombinant human prolactin improves antitumor effecst of murine natural killer cells in vitro and in vivo","volume":"10","author":"Sun","year":"2002","journal-title":"Neuroimmunomodulation"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2004.10.008","article-title":"Antitumor effects of recombinant human prolactin in human adenocarcinoma-bearing SCID mice with human NK cell xenograft","volume":"5","author":"Zhang","year":"2005","journal-title":"Int Immunopharmacol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2004.02686.x","article-title":"Effects of prolactin and cortisol on natural killer (NK) cell surface expression and function of human natural cytotoxicity receptors (NKp46, NKp44 and NKp30)","volume":"139","author":"Mavoungou","year":"2005","journal-title":"Clin Exp Immunol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1586062\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T04:13:45Z","timestamp":1758600825000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1586062\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,23]]},"references-count":59,"alternative-id":["10.3389\/fendo.2025.1586062"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1586062","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,23]]},"article-number":"1586062"}}