{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:58:26Z","timestamp":1785430706531,"version":"3.56.0"},"reference-count":63,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01CA022443, R35CA210807"],"award-info":[{"award-number":["P01CA022443, R35CA210807"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wisconsin Partnership Program","award":["7859-2026"],"award-info":[{"award-number":["7859-2026"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Persistent papillomavirus infection is a key driver of neoplastic progression in both mucosal and cutaneous epithelia. Although estrogen is a well-established cofactor in HPV-associated cervical carcinogenesis, its role in cutaneous papillomavirus disease has remained poorly understood. Using a murine papillomavirus type 1 (MmuPV1) infection model in immunocompetent\n                      <jats:italic toggle=\"yes\">FVB\/N<\/jats:italic>\n                      mice, we investigated whether estrogen influences viral pathogenesis in infected cutaneous epithelia. Estrogen treatment significantly increased wart incidence and growth independent of sex and was associated with pronounced epithelial hyperplasia, dysplasia, koilocytosis, and features of invasive squamous cell carcinoma. Systemically, estrogen reduces circulating leukocytes, while locally suppressing adaptive immune infiltration and enriching neutrophils within lesions, indicating broad immunosuppression coupled with selective innate enhancement. MmuPV1 E1^E4 and L1 RNA and protein levels were elevated in warts of estrogen-treated WT mice, indicative of enhanced productive infection. Importantly,\n                      <jats:italic toggle=\"yes\">Esr1<\/jats:italic>\n                      germline knockout mice exhibited significantly reduced wart incidence and size in both males and females, lower MmuPV1 E1^E4 and L1 transcript levels, coupled with the absence of estrogen-induced depletion of circulating immune cells, demonstrating that ER\u03b1 signaling mediates estrogen-driven epithelial proliferation, immune modulation, disease progression, and productive viral infection. Collectively, these novel findings indicate that estrogen is a potent cofactor in cutaneous papillomavirus disease, acting through ER\u03b1-dependent pathways to drive virally -induced neoplastic diseases, including cancer.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Papillomaviruses are major causes of cancer in both women and men, yet the factors that influence disease severity remain incompletely understood. While estrogen is known to cooperate with papillomaviruses to drive cervical cancer, its role in papillomavirus-associated skin disease has not been defined. Our study demonstrates that estrogen significantly amplifies papillomavirus-induced skin pathology in both male and female mice, increasing the frequency, size, and severity of epidermal lesions. These findings reveal a previously unrecognized hormonal influence on cutaneous papillomavirus disease and suggest that sex hormones may broadly modulate papillomavirus-associated cancers beyond the reproductive tract.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00783-26","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:00:48Z","timestamp":1780059648000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Estrogen receptor \u03b1 (\n                    <i>Esr1<\/i>\n                    ) mediates estrogen\u2019s ability to promote papillomavirus-induced cutaneous disease in male and female mice"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5519-9518","authenticated-orcid":true,"given":"Sheikh A.","family":"Umar","sequence":"first","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9575-489X","authenticated-orcid":false,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]},{"id":[{"id":"https:\/\/ror.org\/05hs6h993","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology, Genetics, & Immunology, Michigan State University","place":["East Lansing, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghwan","family":"Jeon","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lam Khue","family":"Pham","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella T.","family":"Ward-Shaw","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Lee","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01y2jtd41","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]},{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bilger","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9753-6615","authenticated-orcid":true,"given":"Megan E.","family":"Spurgeon","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]},{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]},{"id":[{"id":"https:\/\/ror.org\/05cb4rb43","id-type":"ROR","asserted-by":"publisher"}],"name":"John W. and Jeanne M. Rowe Center for Research in Virology, Morgridge Institute for Research","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7983-2755","authenticated-orcid":true,"given":"Paul F.","family":"Lambert","sequence":"additional","affiliation":[{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]},{"id":[{"id":"https:\/\/ror.org\/01e4byj08","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2016.0273"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.06.083"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00355"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddmod.2005.05.021"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-025-06470-x"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911436106"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1610-0387.2009.06988.x"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers18040636"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712018114"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409883102"},{"key":"e_1_3_6_12_2","first-page":"1267","article-title":"Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis","volume":"60","author":"Elson DA","year":"2000","unstructured":"Elson DA, Riley RR, Lacey A, Thordarson G, Talamantes FJ, Arbeit JM. 2000. Sensitivity of the cervical transformation zone to estrogen-induced squamous carcinogenesis. Cancer Res 60:1267\u20131275.","journal-title":"Cancer Res"},{"key":"e_1_3_6_13_2","unstructured":"Girone C. 2024. Targeted therapeutic strategies for HPV-associated cancers: molecular mechanisms and promising approaches. https:\/\/iris.uniupo.it\/handle\/11579\/212382."},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2051"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00180-19"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00002-20"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviromet.2017.12.002"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/v14051000"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120128"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.000926"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2015.10.030"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/v9090246"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00777-13"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14040909"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2214225120"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00933-24"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-019-0935-6"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.7.2930"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.19.4277"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.3390\/v12040450"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012472"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006715"},{"key":"e_1_3_6_33_2","first-page":"4862","article-title":"Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis","volume":"63","author":"Riley RR","year":"2003","unstructured":"Riley RR, Duensing S, Brake T, M\u00fcnger K, Lambert PF, Arbeit JM. 2003. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res 63:4862\u20134871.","journal-title":"Cancer Res"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","unstructured":"Bilger A Ward-Shaw ET Lee DL King RE Newton MA Buehler D Matkowskyj KA Sundberg JP Hu R Lambert PF. 2024. Invasive cancer and spontaneous regression two weeks after papillomavirus infection. bioRxiv:2024.09.04.611275. doi:10.1101\/2024.09.04.611275","DOI":"10.1101\/2024.09.04.611275"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens14050464"},{"key":"e_1_3_6_36_2","unstructured":"Fracella M. 2025. Microbial co-infections and innate immune responses in human papillomavirus mucosal infections: insights from in vivo and in vitro models"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1155\/2007\/613150"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13091824"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgt350"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.2174\/1871520618666180830162517"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32500"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2010.03.005"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00617-5"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1072-7515(00)00578-0"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-012-0125-7"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.3390\/v9080219"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.649815"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2015.01.018"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.90"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008206"},{"key":"e_1_3_6_51_2","unstructured":"Saunders-Wood T. 2020. Investigating early lesion formation following papillomavirus infection using a mouse model and cell culture"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2015.3295"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpobgyn.2017.08.001"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1556728"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.4081\/oncol.2012.e17"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13027-016-0107-4"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9050403"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2014.11"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2021.06.012"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-02043-4"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.25.022106.141634"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1136\/sextrans-2014-051601"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/92.9.709"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00783-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.00783-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:03:11Z","timestamp":1783515791000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.00783-26"}},"subtitle":[],"editor":[{"given":"Carolyn B.","family":"Coyne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":63,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,8]]}},"alternative-id":["10.1128\/mbio.00783-26"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00783-26","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]},"assertion":[{"value":"2026-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00783-26"}}