Vaginal Squamous Cell Carcinoma Develops in Mice with Conditional Arid1a Loss and Gain of Oncogenic Kras Driven by Progesterone Receptor Cre

Wang, Xiyin; Praça, Mariana S. L.; Wendel, Jillian R. H.; Emerson, Robert E.; DeMayo, Francesco J.; Lydon, John P.; Hawkins, Shannon M.

doi:10.1016/j.ajpath.2021.03.013

Cited by 5 publications

(5 citation statements)

References 59 publications

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“…We observed that ARID1A mutant UCEC tumors have higher TP63 expression than TP53 mutant tumors. A recent mouse model of ARID1A deletion paired with oncogenic KRAS G12D developed invasive vaginal squamous cell carcinoma [104]. TP63+ squamous differentiation in invasive endometrial cancer was also recently reported in a subset of Fbxw7/Pten knockout mice [81].…”

Section: Plos Geneticsmentioning

confidence: 71%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

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TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

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Section: Plos Geneticsmentioning

confidence: 71%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

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“…Concordant with the current study, they successfully rescued the phenotype through estrogen administration using silastic capsules [ 29 ]. Furthermore, studies have shown estrogen mediates the development of mutant- Kras -driven endometrial cancer, ovarian cancer and vaginal SCC [ 30 – 32 ]. It has been shown that ERα is present in 4% of human anal SCC samples [ 27 ] and that estrogen is essential for activating cell proliferation of human epithelial SCC cell lines [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Estrogen dependence of anal SCC formation. Estrogen has a known role in the development of several tumors [27][28][29][30][31][32] and a correlation with Kras-mutant cancer [29][30][31][32]. Thus, we tested whether the anal SCC tumor development in a papillomavirus-negative context was driven by estrogen.…”

Section: Plos Onementioning

confidence: 99%

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

et al. 2021

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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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“…[28] Furthermore, studies have shown estrogen mediates the development of mutant-Kras-driven endometrial cancer, ovarian cancer and vaginal SCC. [29][30][31] It has been shown…”

Section: Discussionmentioning

confidence: 99%

“…This remarkable finding indicates that female sex hormones are crucial for Kras G12D -driven anal SCC development in KC mice. Estrogen has a known role in the development of several tumors [26][27][28][29][30][31] and a correlation with Kras-mutant cancer [28][29][30][31]. Thus, we tested whether the anal SCC tumor development in a papillomavirus-negative context was driven by estrogen.…”

Section: Sex Hormone Dependence Of Anal Scc Formationmentioning

confidence: 99%

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

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Turco

Blaine-Sauer

et al. 2021

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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 a 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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Vaginal Squamous Cell Carcinoma Develops in Mice with Conditional Arid1a Loss and Gain of Oncogenic Kras Driven by Progesterone Receptor Cre

Cited by 5 publications

References 59 publications

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

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

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

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