Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice

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 an...

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Autores principales:	Morgan T. Walcheck, Kristina A. Matkowskyj, Anne Turco, Simon Blaine-Sauer, Manabu Nukaya, Jessica Noel, Oline K. Ronnekleiv, Sean M. Ronnekleiv-Kelly
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/07735900d8a84f98a147a141e4fd04f7
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spelling	oai:doaj.org-article:07735900d8a84f98a147a141e4fd04f72021-11-11T07:14:35ZSex-dependent development of Kras-induced anal squamous cell carcinoma in mice1932-6203https://doaj.org/article/07735900d8a84f98a147a141e4fd04f72021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8568287/?tool=EBIhttps://doaj.org/toc/1932-6203Anal 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.Morgan T. WalcheckKristina A. MatkowskyjAnne TurcoSimon Blaine-SauerManabu NukayaJessica NoelOline K. RonnekleivSean M. Ronnekleiv-KellyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Morgan T. Walcheck Kristina A. Matkowskyj Anne Turco Simon Blaine-Sauer Manabu Nukaya Jessica Noel Oline K. Ronnekleiv Sean M. Ronnekleiv-Kelly Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice
description	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.
format	article
author	Morgan T. Walcheck Kristina A. Matkowskyj Anne Turco Simon Blaine-Sauer Manabu Nukaya Jessica Noel Oline K. Ronnekleiv Sean M. Ronnekleiv-Kelly
author_facet	Morgan T. Walcheck Kristina A. Matkowskyj Anne Turco Simon Blaine-Sauer Manabu Nukaya Jessica Noel Oline K. Ronnekleiv Sean M. Ronnekleiv-Kelly
author_sort	Morgan T. Walcheck
title	Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice
title_short	Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice
title_full	Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice
title_fullStr	Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice
title_full_unstemmed	Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice
title_sort	sex-dependent development of kras-induced anal squamous cell carcinoma in mice
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/07735900d8a84f98a147a141e4fd04f7
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Sex-dependent development of Kras-induced anal squamous cell carcinoma in mice

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