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Therapeutic advances are slow, largely due to the absence of animal models for translational research. Here, we report the first mouse model for HPV\u2010related penile cancer. Ten\u2010week\u2010old mice expressing all the HPV16 early genes under control of the cytokeratin 14 (<jats:italic>Krt14<\/jats:italic>) gene promoter and matched wild\u2010type controls were exposed topically to dimethylbenz(a)anthracene (DMBA) or vehicle for 16\u2009weeks. At 30\u2009weeks of age, mice were sacrificed for histological analysis. Expression of Ki67, cytokeratin 14, and of the HPV16 oncogenes <jats:italic>E6<\/jats:italic> and <jats:italic>E7<\/jats:italic> was confirmed using immunohistochemistry and quantitative PCR, respectively. HPV16\u2010transgenic mice developed intraepithelial lesions including condylomas and penile intraepithelial neoplasia (PeIN). Lesions expressed cytokeratin 14 and the HPV16 oncogenes <jats:italic>E6<\/jats:italic> and <jats:italic>E7<\/jats:italic> and showed deregulated cell proliferation, demonstrated by Ki67\u2010positive supra\u2010basal cells. HPV16\u2010transgenic mice exposed to DMBA showed increased PeIN incidence and squamous cell carcinoma. Malignant lesions showed varied histological features closely resembling those of HPV\u2010associated human penile cancers. Wild\u2010type mice showed no malignant or pre\u2010malignant lesions even when exposed to DMBA. These observations provide the first experimental evidence to support the etiological role of HPV16 in penile carcinogenesis. Importantly, this is the first mouse model to recapitulate key steps of HPV\u2010related penile carcinogenesis and to reproduce morphological and molecular features of human penile cancer, providing a unique <jats:italic>in vivo<\/jats:italic> tool for studying its biology and advancing basic and translational research. \u00a9 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5475","type":"journal-article","created":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T04:41:01Z","timestamp":1591159261000},"page":"411-419","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["<scp>HPV16<\/scp> induces penile intraepithelial neoplasia and squamous cell carcinoma in transgenic mice: first mouse model for <scp>HPV<\/scp>\u2010related penile cancer"],"prefix":"10.1002","volume":"251","author":[{"given":"Beatriz","family":"Medeiros\u2010Fonseca","sequence":"first","affiliation":[{"name":"CITAB, Universidade de Tr\u00e1s\u2010os\u2010Montes e Alto Douro, UTAD  Vila Real Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica F","family":"Mestre","sequence":"additional","affiliation":[{"name":"CITAB, Universidade de Tr\u00e1s\u2010os\u2010Montes e Alto Douro, UTAD  Vila Real 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J","family":"Fern\u00e1ndez\u2010Nestosa","sequence":"additional","affiliation":[{"name":"Instituto de Patolog\u00eda e Investigaci\u00f3n and Universidad Nacional de Asunci\u00f3n  Asunci\u00f3n Paraguay"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F\u00e1tima","family":"Casaca","sequence":"additional","affiliation":[{"name":"Botelho Moniz An\u00e1lises Cl\u00ednicas (BMAC)  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Silva","sequence":"additional","affiliation":[{"name":"Botelho Moniz An\u00e1lises Cl\u00ednicas (BMAC)  Porto Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haissa","family":"Brito","sequence":"additional","affiliation":[{"name":"Biobanco de Tumores e DNA do Maranh\u00e3o, PPGSAD, Universidade Federal do Maranh\u00e3o (UFMA)  S\u00e3o Lu\u00eds 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