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Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice.
Walcheck, Morgan T; Matkowskyj, Kristina A; Turco, Anne; Blaine-Sauer, Simon; Nukaya, Manabu; Noel, Jessica; Ronnekleiv, Oline K; Ronnekleiv-Kelly, Sean M.
Afiliación
  • Walcheck MT; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, United States of America.
  • Matkowskyj KA; University of Wisconsin Carbone Cancer Center, Madison, WI, United States of America.
  • Turco A; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
  • Blaine-Sauer S; William S. Middleton Memorial Veterans Hospital, Madison, WI, United States of America.
  • Nukaya M; Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
  • Noel J; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, United States of America.
  • Ronnekleiv OK; Division of Surgical Oncology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States of America.
  • Ronnekleiv-Kelly SM; McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI, United States of America.
PLoS One ; 16(11): e0259245, 2021.
Article en En | MEDLINE | ID: mdl-34735515
Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (~85-95%), with approximately 5-15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized the Kras-driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-KrasG12D; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant KrasG12D gene. Although the driver gene mutation KrasG12D is present in anus of both sexes, only female KC mice develop Kras-mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias del Ano / Carcinoma de Células Escamosas / Transactivadores / Proteínas Proto-Oncogénicas p21(ras) / Proteínas de Homeodominio Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias del Ano / Carcinoma de Células Escamosas / Transactivadores / Proteínas Proto-Oncogénicas p21(ras) / Proteínas de Homeodominio Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos