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Uterine Double-Conditional Inactivation of Smad2 and Smad3

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Uterine Double-Conditional Inactivation of Smad2 and Smad3 Uterine double-conditional inactivation of Smad2 and SEE COMMENTARY Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer Maya Krisemana,b, Diana Monsivaisa,c, Julio Agnoa, Ramya P. Masanda, Chad J. Creightond,e, and Martin M. Matzuka,c,f,g,h,1 aDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; bReproductive Endocrinology and Infertility, Baylor College of Medicine/Texas Children’s Hospital Women’s Pavilion, Houston, TX 77030; cCenter for Drug Discovery, Baylor College of Medicine, Houston, TX 77030; dDepartment of Medicine, Baylor College of Medicine, Houston, TX 77030; eDan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030; fDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; gDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; and hDepartment of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030 Contributed by Martin M. Matzuk, December 6, 2018 (sent for review April 30, 2018; reviewed by Milan K. Bagchi and Thomas E. Spencer) SMAD2 and SMAD3 are downstream proteins in the transforming in endometrial function. Notably, members of the transforming growth factor-β (TGF β) signaling pathway that translocate signals growth factor β (TGF β) family are involved in many cellular from the cell membrane to the nucleus, bind DNA, and control the processes and serve as principal regulators of numerous biological expression of target genes. While SMAD2/3 have important roles functions, including female reproduction. Previous studies have in the ovary, we do not fully understand the roles of SMAD2/3 in shown the TGF β family to have key roles in ovarian folliculo- the uterus and their implications in the reproductive system. To genesis and ovulation (13, 14), decidualization (15, 16), implan- avoid deleterious effects of global deletion, and given previous tation (17, 18), placentation (17, 19), uterine receptivity (15), and data showing redundant function of Smad2 and Smad3, a double- uterine development (20, 21), with disruption in the TGF β family conditional knockout was generated using progesterone receptor- causing reproductive diseases and cancer (22–25). cre (Smad2/3 cKO)mice.Smad2/3 cKO mice were infertile due to SMAD2 and SMAD3 are downstream proteins in the TGF β endometrial hyperproliferation observed as early as 6 weeks of signaling family that are important in translocating signals to the PHYSIOLOGY postnatal life. Endometrial hyperplasia worsened with age, and nucleus, binding DNA, and regulating the expression of target all Smad2/3 cKO mice ultimately developed bulky endometrioid- genes. Previous studies in mouse models have shown that de- type uterine cancers with 100% mortality by 8 months of age. letion of the type 1 TGF β receptor (ALK5) upstream of The phenotype was hormone-dependent and could be prevented SMAD2/3 results in fertility defects (17, 26) and that when de- with removal of the ovaries at 6 weeks of age but not at 12 weeks. letion is combined with PTEN inactivation (a tumor suppressor), Uterine tumor epithelium was associated with decreased expres- sion of steroid biosynthesis genes, increased expression of inflam- Significance matory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 Endometrial hyperplasia, a result of unopposed estrogen, in maintaining normal endometrial function and confirm the hormone- changes the uterine environment. This overgrowth of uterine dependent nature of SMAD2/3 in the uterus. The hyperproliferation of lining can progress to uterine cancer and disrupt uterine re- the endometrium affected both implantation and maintenance of preg- ceptivity and implantation. However, fertility-preserving pro- nancy. Our findings generate a mouse model to study the roles of gesterone therapy for early endometrial carcinoma and SMAD2/3 in the uterus and serve to provide insight into the mechanism atypical endometrial hyperplasia does not always result in by which the endometrium can escape the plethora of growth resolution. Therefore, a better understanding of the mech- regulatory proteins. anisms by which the endometrium is regulated is prudent for both fertility and cancer therapy. We generated a condi- TGF β signaling | uterine hyperplasia | endometrial cancer | tional knockout of Smad2/3 in the uterus and demonstrated female reproduction | knockout mouse that Smad2/3 plays a critical role in the endometrium, with disruption resulting in pubertal-onset uterine hyperplasia he endometrium is a dynamic tissue that is continuously and, ultimately, lethal uterine cancer. Our findings provide a Tchanging in response to hormonal expression and requires a mouse model to investigate transforming growth factor-β delicate interplay of cellular and molecular events. Defects in the signaling in reproduction and cancer and advance our un- regulation of the endometrium can have serious implications in derstanding of endometrial pathogenesis. women. About 10% of women (∼6.1 million) in the United States aged 15–44 y have difficulty getting pregnant or staying pregnant (1), Author contributions: M.K., D.M., and M.M.M. designed research; M.K., D.M., and J.A. with defects in the endometrium being implicated in cases of poor performed research; M.K., D.M., R.P.M., C.J.C., and M.M.M. analyzed data; and M.K., D.M., and M.M.M wrote the paper. implantation, pregnancy loss, and placental abnormalities. Endome- trial hyperplasia changes the uterine environment, thereby affecting Reviewers: M.K.B., University of Illinois; and T.E.S., University of Missouri. implantation and pregnancy, and can progress to uterine cancer, the Conflict of interest statement: D.M. and T.E.S. are coauthors on a 2015 Commentary article. most commonly diagnosed gynecological cancer in the United States, This open access article is distributed under Creative Commons Attribution-NonCommercial- NoDerivatives License 4.0 (CC BY-NC-ND). affecting ∼50,000 women each year (2). However, fertility-sparing Data deposition: The RNA sequencing data reported in this paper have been deposited in progesterone therapy for early endometrial carcinoma and atypical the Gene Expression Omnibus, https://www.ncbi.nlm.nih.gov/geo (accession no. complex endometrial hyperplasia only results in resolution in ∼40– GSE112664). 80% of patients, with a recurrence risk of ∼20–40% (3–7). Therefore, See Commentary on page 3367. understanding the mechanism by which the endometrium is regu- 1To whom correspondence should be addressed. Email: [email protected]. lated is prudent for both fertility and cancer therapy. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. Several regulatory proteins, growth factors, and their receptors 1073/pnas.1806862116/-/DCSupplemental. (8–12) have been studied and identified to play an important role Published online January 16, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1806862116 PNAS | February 26, 2019 | vol. 116 | no. 9 | 3873–3882 Downloaded by guest on September 23, 2021 it promotes aggressive endometrial cancer progression (27). Table 1. Six-month mating study Likewise, the role of SMAD2/3 in the ovary has previously been Genotype Females Litters Pups per litter Litters per month characterized, showing defects in follicular development, ovula- tion, and cumulus cell expansion (14). In humans, abnormal ex- Control 12 65 6.4 ± 1.9 0.8 ± 0.3 pression of TGF β receptors has also been shown in endometrial Smad2/3 cKO 11 1 2* 0.01 cancer (28, 29), with SMAD2/3 specifically being implicated in *One female had one litter. several human tumors, including colon (24) and pancreas (30) tumors. Despite the growing abundance of TGF β pathway liter- ature, we do not fully understand the roles of SMAD2/3 in the Smad2/3 cKO) with known fertile WT male mice for 6 mo. The uterus and their implications in fertility and uterine cancer. 12 control females had normal breeding activity during the test Mouse models are powerful tools that allow us to investigate period. In contrast, ablation of uterine Smad2/3 led to sterility in gene function in vivo and provide us with a better understanding of 10 of the 11 females tested. The remaining female had one initial uterine regulation. Global knockout of Smad2 is embryonic lethal litter of two pups in the first month of breeding, with no subsequent in mice (31, 32), whereas global knockout of Smad3 results in ul- litters or offspring. Vaginal plugs were observed at similar frequen- timate death postnatally (33, 34). Therefore, conditional deletion cies between the two genotypes, which eliminated the possibility of of Smad2/3 in the uterine stroma and endometrium was obtained abnormal mating behavior. Compared with the controls, uteri from using a progesterone receptor-cre (Pgr-cre) mouse model (35). the Smad2/3 cKO mice had fewer implantation sites (Fig. 1A), with a Deletion of uterine Smad2/3 led to uterine hyperplasia, which trend toward smaller weight per implantation site (Fig. 1B). Hem- resulted in infertility and eventual lethal uterine tumor forma- orrhagic implantation sites were also noted at 10.5 d post coitum tion. Therefore, elucidating the role of SMAD2/3 in the endo- (dpc) in the Smad2/3 cKO mice, suggesting poor placentation. metrium will uncover the mechanism by which the endometrium In Pgr-cre transgenic mice, Cre is also expressed in the gran- can escape the abundance of growth regulatory
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