Journal Article

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

Turco, Anne, Ronnekleiv-Kelly, Sean M., Noel, Jessica, Blaine-Sauer, Simon, Matkowskyj, Kristina A., Walcheck, Morgan T., Ronnekleiv, Oline K., Nukaya, Manabu

2021

Overview

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-Kras G12D ; 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 Kras G12D gene. Although the driver gene mutation Kras G12D 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anal cancer / Analysis / Animal models in research / Animals / Anus / Anus Neoplasms - genetics / Anus Neoplasms - metabolism / Anus Neoplasms - pathology / Biology and Life Sciences / Cancer / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Carcinoma, Squamous Cell - pathology / Chemoradiotherapy / Colorectal cancer / Demographic aspects / Estrogens / Estrogens - metabolism / Etiology / Female / Females / Genetic aspects / Gynecological cancer / Histology / Homeodomain Proteins - genetics / Hormones / Human papillomavirus / Infections / K-Ras protein / Laboratory animals / Male / Males / Medical research / Medicine / Medicine and Health Sciences / Mice / mRNA / Mutants / Mutation / Nutrition research / Oncology / Ovarian cancer / Ovariectomy / Pathogenesis / Pathology / Patients / Phenotypes / Point mutation / Proto-Oncogene Proteins p21(ras) - genetics / Public health / Recombinase / Research and Analysis Methods / Sex Factors / Sex hormones / Sexes / Squamous cell carcinoma / Surgery / Trans-Activators - genetics / Tumors