Tumorigenic potential of pituitary tumor transforming gene (PTTG) in vivoinvestigated using a transgenic mouse model, and effects of cross breeding with p53 (+/−) transgenic mice
© Fong et al.; licensee BioMed Central Ltd. 2012
Received: 16 May 2012
Accepted: 8 November 2012
Published: 20 November 2012
Pituitary tumor-transforming gene (PTTG) is an oncogene that is overexpressed in variety of tumors and exhibits characteristics of a transforming gene. Previous transgenic mouse models to access the tumorigenic potential in the pituitary and ovary have resulted in dysplasia without formation of visible tumors, possibly due to the insufficient expression of PTTG. PTTG expression level is critical for ovarian tumorigenesis in a xenograft model. Therefore, the tumorigenic function of PTTG in vivo remains unclear. We generated a transgenic mouse that overexpresses PTTG driven by the CMV promoter to determine whether PTTG functions as a transforming oncogene that is capable of initiating tumorigenesis.
Transgenic animals were generated by microinjection of PTTG transgene into the male pronucleus of FVB 0.5 day old embryos. Expression levels of PTTG in tissues of transgenic animals were analyzed using an immunohistochemical analysis. H&E staining and immunohistostaining were performed to examine the type of tumor in transgenic and PTTG transgenic/p53+/- animals.
PTTG transgenic offspring (TgPTTG) were monitored for tumor development at various ages. H&E analysis was performed to identify the presence of cancer and hyperplastic conditions verified with the proliferation marker PCNA and the microvessel marker CD31. Immunohistochemistry was performed to determine transgene expression, revealing localization to the epithelium of the fallopian tube, with more generalized expression in the liver, lung, kidney, and spleen. At eight months of age, 2 out of 15 TgPTTG developed ovarian cancer, 2 out of 15 developed benign tumors, 2 out of 15 developed cervical dysplasia, and 3 out of 15 developed adenomyosis of the uterus. At ten months of age, 2 out of 10 TgPTTG developed adenocarcinoma of the ovary, 1 out of 10 developed a papillary serous adenocarcinoma, and 2 out of 10 presented with atypia of ovarian epithelial cells. Tumorigenesis is a multi-step process, often requiring multiple oncogenes and/or inactivation of tumor suppressor genes. Therefore, to understand the contribution of p53 to PTTG induced tumorigenesis, we crossbred TgPTTG to p53+/− mice and maintained those 8 to 10 months. TgPTTG/p53+/− animals developed sarcomas faster than p53+/− alone as well as different tumor types in addition to cervical carcinomas in situ in 10 out of 17 females.
We conclude that while PTTG is a functional transforming oncogene, it requires an additional partner to effectively promote tumorigenesis through the loss of p53 include or between function or modulation.
KeywordsPTTG Transgenic mice p53 Tumorigenesis Cancer
The pituitary tumor transforming gene (PTTG), also known as securin, is ubiquitously expressed at a low basal level where it functions in regulating sister chromatid separation . Its physiologic functions include cell proliferation, ensuring the fidelity of DNA replication, DNA damage repair, organ development, and metabolism . Overexpression of PTTG influences multiple pathways for cancer initiation and progression including enhanced cell proliferation , genomic instability , and cellular transformation [3, 5]. Its transforming ability has been demonstrated in vitro where over-expression of PTTG induces anchorage-independent growth in soft agar and in vivo xenograft tumor formation in nude mice using rat fibroblast NIH3T3 cells and human embryonic kidney HEK293 cells [3, 5]. PTTG overexpression has been correlated with the promotion of angiogenesis through increased expression and secretion of several factors including basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8) [3, 6, 7]. PTTG is implicated in metastasis through the induction of the epithelial to mesenchymal transition [8, 9].
PTTG overexpression has been identified in a variety of endocrine-related tumors, including pituitary, ovarian, uterine, breast, and thyroid [5, 6, 10, 11] and non-endocrine related tumors such as lung, gastrointestinal, and gliomas. PTTG expression is also detected in germ cell tumors, sex-cord and stromal cell tumors, epithelial tumors arising from the ovary and in multiple types of breast cancer, including invasive ductal carcinomas, ductal in situ carcinomas, and infiltrating ductal carcinomas . In pituitary adenomas, PTTG is implicated in tumor initiation and progression . It has also been identified as an oncogene in pituitary tumors activated in the early stages of cellular transformation, from normal to hyperplastic , and has been correlated with tumor invasiveness . Levels of PTTG expression have also been correlated to the degree of malignancy, pathogenesis, and progression of colorectal, thyroid, and breast tumors [14–16]. In the case of gliomas, PTTG has been correlated to poor prognosis in patients . PTTG is abundantly expressed in several carcinoma cell lines including cervical carcinoma HeLa cells, choriocarcinomas JEG-3 and JAR, breast adenocarcinoma MCF-7, osteogenic sarcoma U-2OS, hepatocellular carcinoma Hep 3B, lung carcinoma H1299, EY and A549, ovarian CAOV3 and A2780, and thyroid carcinoma TC-1 [18, 19]. These finding indicate that PTTG may be involved in transformation of several tissues leading to tumorigenesis.
Transgenic PTTG−/− mice exhibit pituitary hypoplasia and, upon cross-breeding with heterozygous deletion of retinoblastoma (Rb+/−), show a tumor development rate of 30%. Comparatively Rb+/−/PTTG+/+ develop tumors at 86% by 13 months of age . PTTG silencing using siRNA on xenograft tumors from an ovarian cancer cell line and hepatocellular carcinoma cell line reduced both the size and incidence of tumor burden; however, incomplete silencing of PTTG led to a reduction of tumor burden, while complete silencing showed nearly complete eradication of tumors, indicating that PTTG expression impacts tumor formation and tumor growth [19, 21].
Previously, our lab developed a transgenic mouse model that over-expresses human PTTG cDNA under the control of Müllerian inhibiting substance type II receptor (MISIIR). These mice presented with an increased mass of the corpus luteum as well as an increase in serum LH and testosterone, but failed to generate visible ovarian tumors , possibly due to a weak promoter that was unable to produce the required level of PTTG protein to initiate tumorigenesis. In addition, Abbud et al.  generated a PTTG transgenic mouse under the control of the alpha-subunit of glycoprotein hormone (αGSU) to target expression to the gonadotroph cells of the pituitary, resulting in gonadroph hyperplasia and microadenomas with plurihormal hyperplasia, accompanied by prostatic and seminal vesicle hyperplasia. Tumorigenesis often requires multiple gene mutations including activation or amplification of oncogenes, increased growth factors and their receptors, and/or inactivation of tumor suppressor genes. As such, PTTG expression by itself may not be sufficient to drive tumorigenesis and may require a partner gene . Therefore, in our current study, we have selected the CMV promoter to drive expression of human PTTG cDNA to produce PTTG transgenic (TgPTTG) mice to understand the tumorigenic potential of PTTG in vivo. In addition, we crossbred TgPTTG with p53+/− mice. TgPTTG mice developed ovarian adenocarcinomas and adenocarcinoma of the fallopian tube. Crossbreeding of TgPTTG with p53+/− mice resulted in enhanced tumor incidence, earlier tumor formation, and carcinomas in situ of the cervix.
Construction of CMV-PTTG-EGFP transgene
Mice were housed in a conventional facility with a 12 h light: 12 h darkness cycle and fed standard chow and water ad libdum. All animals were treated in accordance with National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and approved by Institutional Animal Care and Use Committee (IACUC) at the University of Louisville.
Generation of transgenic animals
Transgenic animals were generated in association with the University of Cincinnati Transgenic Mouse Core Facility. Transgene DNA was microinjected into the male pronucleus of FVB 0.5 day old embryos. Embryos were then transplanted into a pseudo-pregnant female. Wild type males were bred to positive TgPTTG female founders. TgPTTG F1 males were bred to wild type females to establish a colony line.
P53+/− mice on an FVB background were obtained from Jackson Laboratory. Female p53+/− were crossbred with male TgPTTG mice from the same founder line (#71309) to generate TgPTTG/p53+/− mice.
Genotyping and screening of transgenic and p53+/−mice
Mice were tail clipped between 21–28 days of age and toe tattooed with an ID number. DNA from tail clips was extracted using PCR Extract-N-Amp kit (Sigma). PTTG-EGFP genotype was identified via PCR using the specific primer: PTTG 16182: sense 5’-ACT GAG AAG ACT GTT AAA GC-3’ or PTTG 16207: sense 5’-ACG AAT TCA TGG CTA CTC TGA TCT ATG T-3’, and EGFP antisense 23759: 5’- AGA TGA ACT TCA GGG TCA GC-3’ that specifically amplified the transgene sequence (Figure 1). Two PTTG sense primers were used to verify accuracy of amplification. PCR conditions were 1) 94°C for 5 min, 2) 94°C for 30 sec, 3) 58°C for 30 sec, 4) 72°C for 1 min, 5) steps 2–4 were repeated for 30 cycles, 6) 72°C for 7 min. P53+/− genotype was identified via PCR using the specific primers according to Jackson Laboratory protocol: Wild type: sense 5’-ACA GCG TGG TAC CTT AT-3’, Common: antisense 5’- TAT ACT CAG AGC CGG CCT -3’, and Mutant: sense 5’-CTA TCA GGA CAT AGC GTT GG-3’. PCR conditions were 1) 94°C for 3 min, 2) 94°C for 30 sec, 3) 64°C for 1 min, 4) 72°C for 1.5 min, 5) Steps 2–4 repeated for 35 cycles, 6) 72°C for 2 min.
RNA isolation and analysis of transgene expression via RT-PCR
Tissues were preserved in RNA Later (Sigma) at the time of sacrificing. Tissues were homogenized in 1 ml of Trizol (Sigma) and isolated via standard procedures. Total RNA was quantitated by NanoDrop. One μg of total RNA was converted to cDNA using a reverse transcription kit (BioRad). Total cDNA was then subjected to PCR amplification as described above.
Tissues samples were fixed in 10% neutral buffered formalin (Fisher Scientific) overnight at RT. After 24 h, formalin was then replaced with 70% ethanol and the tissues were stored at 4°C until processing. Tissues were embedded in paraffin using standard techniques. Five micrometer sections were stained with H&E by the Pathology Core Research Laboratory, University of Louisville and evaluated by a trained pathologist, Hanan Farghaly, MD.
Formalin-fixed paraffin embedded tissue sections were deparaffinized in fresh xylene and rehydrated in a graded series of ethanol. Antigen retrieval was conducted by incubating the slides in 10 mM sodium citrate (pH 6.0) at 95°C for 20 min then rinsing twice with PBS. Slides were incubated in 4 drops per section of Image-It FX Signal Enhancer (Invitrogen) for 30 min in a humidity chamber and then rinsed with PBS. Slides were blocked with 10% goat serum (Sigma) in PBS for 1 h followed by anti-PTTG diluted 1:1,500 in PBS and incubated at 4°C overnight. Slides were then washed in PBS before application of a secondary Alexa 594 labeled anti-rabbit (Invitrogen) diluted 1:500 in PBS containing 1 drop of goat serum per 5 ml and incubated for 45 min at RT in the dark, then washed three times with PBS. Images were acquired on Nikon Eclipse E400 and ACT-1.1 imaging software (Huntley, IL, USA).
Formalin-fixed paraffin embedded tissues were deparaffinized in xylene and rehydrated in a decreasing graded series of ethanol. Antigen retrieval was conducted by incubating the slides in 10 mM sodium citrate (pH 6.0) at 95°C for 20 min, then rinsed in PBS for 5 min. Slides were incubated with 0.3% hydrogen peroxide in methanol for 20 min at RT and rinsed three times in PBS for 5 min each. For proliferating cell nuclear antigen (PCNA) expression, slides were blocked using a Mouse-On-Mouse (M.O.M.) peroxidase kit (Vector Laboratories) for 1 h at RT. Blocking solution was poured off and slides were incubated in M.O.M. diluent for 5 minutes. PCNA diluted 1:2,000 (Cell Signaling) in SignalStain antibody diluent (Cell Signaling) was incubated overnight at 4°C. After washing three times in PBS for 5 min each, secondary anti-mouse biotinylated IgG from M.O.M. kit was incubated for 45 min at RT followed by 30 min incubation with streptavidin. After three washes in PBS for 5 min each, 3, 3’-diaminobenzidine (DAB, Vector Laboratories) was used to develop color. For CD31, slides were blocked using Vectastain anti-rabbit Elite ABC kit (Vector Laboratories) for 1 h at RT and then incubated with anti-CD31 (1:50, AbCam) in PBS overnight at 4°C. Vectastain anti-rabbit Elite ABC kit (Vector Laboratories) and DAB was used to develop color.
Generation of CMV-PTTG-EGFP transgenic mice
Breeding summary of TgPTTG founders
Number of breeding
Total number of offspring
Number of positive mice in F1
PTTG expression in CMV-PTTG-EGFP mice
Histology and immunohistochemistry of TgPTTG tissues
Summary of PCNA and CD31 staining in 8 months old WT and TgPTTG mice
ID# and Tissue
TgPTTG #434 Ovary
TgPTTG #436 Ovary
TgPTTG #286 Cervix
TgPTTG #436 Cervix
WT Fallopian Tube
TgPTTG #365 Fallopian Tube
Summary of PCNA and CD31 staining in 10 months old WT and TgPTTG mice
ID# and Tissue
TgPTTG #381 Ovary
TgPTTG #383 Ovary
WT Fallopian Tube
TgPTTG #381 Fallopian Tube
+ + +
TgPTTG #294 PS AdC
+ + +
Transgene copy number analysis
Although unlikely, the transgene copy number could have been unstable, and therefore vary among offspring. To exclude this possibility, transgene copy number was assessed to analyze differences between TgPTTG that developed cancer and those that did not. A standard curve was generated using the N3 vector containing PTTG (Additional file 1: Figure S 1A). By calculating the size of the vector, a copy number could be assessed to the standard curve. Then, by taking 100 ng of genomic DNA isolated from the tail clip, the gene copy number was extrapolated from the standard curve as 100 ng of DNA has been reported to yield 1.67 x 104 diploid cells . We found no difference in transgene copy number between TgPTTG mice that developed cancer and those that did not develop cancer (Additional file 1: Figure S 1B).
Crossbreeding of TgPTTG with p53+/−mice and histology
P53 mutant mice were produced by a targeted neo cassette insertion into the p53 locus in the laboratory of Dr. Tyler Jacks at the Center for Cancer Research, Massachusetts Institute of Technology  and are commercially available through the Jackson Laboratory. P53+/− mice have been reported to have an 18% incidence of adenocarcinomas and a 56% incidence of sarcomas over a period of 17 months . Based on the 56 mice we observed (45 p53+/− and 11 p53−/−), four p53+/− mice (8.9%) developed sarcomas between 3 to 11 months, while nine p53−/− (81.8%) developed lymphoma and sarcomas at age 9 to 12 weeks before succumbing to their disease.
TgPTTG/p53+/− mice aged to 8 months included 10 females. Of the TgPTTG/p53+/− females aged to 8 months, 4 out of 10 (40%) had severe dysplasia of the cervix resulting in carcinomas in situ (Figure 12) along with 1 out of 10 (10%) developing a sarcoma. PCNA staining for cervical carcinomas in situ showed 10% positive area with reverse maturation and 2+ microvessel formation. PCNA showed 99% positive area in all sarcomas, congruent with the highly aggressive nature of this tumor type.
TgPTTG/p53+/− mice aged to 10 months included 8 females. Five out of 8 (63%) females showed focal to severe cervical dysplasia resulting in carcinomas in situ, and 3 out of 8 (38%) showed dilation of the fallopian tube. Two out of 8 (25%) developed high grade leiomyosarcomas (Figure 12). All TgPTTG/p53+/− sarcomas were 99% positive for PCNA and had significant microvessel formation (CD31 staining 3+) determined by CD31 (Figure 12). Comparatively, p53+/− mice developed sarcomas between 11 to 12 months of age (2 of 28, 7%).
PTTG has been shown in pituitary tumors to have the properties of a transforming gene activated during the early stages of neoplastic transformation, changing the cells from a normal phenotype to hyperplastic . Based on this information, a transgenic mouse expressing PTTG under the control of αGSU promoter to target the expression to the gonadotroph cells of the pituitary was created . This resulted in gonadroph hyperplasia and microadenomas with plurihormal hyperplasia, accompanied by prostatic and seminal vesicle hyperplasia, demonstrating that PTTG was a functional transforming oncogene. Since PTTG is a prominent oncogene in pituitary tumors, many investigators have identified PTTG in several other endocrine-related tumors. Its expression has been detected in endometriod carcinomas and in hyperplastic endometria . In addition to being cloned from ovarian tumors, PTTG has been identified in various ovarian tumor tissues but not in normal ovary . In addition, a mouse xenograft model of ovarian cancer showed that PTTG was crucial for tumor development . Therefore, previously our lab developed a transgenic mouse model that expresses human PTTG cDNA under the control of MISIIR. These mice presented with an increased mass of the corpus luteum as well as an increase in the serum LH and testosterone. However, despite PTTG expression in the ovary and testes, these animals developed cystic glandular hyperplasia but failed to develop visible ovarian adenocarcinomas , possible due to a weak promoter that was unable to produce the required level of PTTG protein to initiate tumorigenesis. However, we also asked if a partner gene was necessary to complete tumorigenesis as it often requires multiple gene mutations including activation or amplification of oncogenes, increased growth factors and their receptors, and/or inactivation of tumor suppressor genes, and therefore PTTG expression by itself may not be sufficient to drive tumorigenesis and may require a partner gene .
Therefore, in our current study to understand the tumorigenic potential of PTTG, we generated a transgenic mouse that constitutively overexpresses PTTG under the control of the non-specific CMV promoter to strengthen PTTG expression as the level of PTTG is critical for tumorigenesis [19, 33]. By using this approach, we were able to generate ovarian tumors in transgenic animals as early as 8 months of age (Figure 7) and continued to observe them at 10 months (Figure 9), albeit at a low incidence of ~17%. It is interesting that although the CMV promoter is a non-specific promoter, ovarian and fallopian tube tumors and papillary serous adenocarcinomas were the only observed tumor types, perhaps due to the site of integration. However, PTTG also has transactivation activity through the presence of Src-homology 3 (SH3) domains located in the proline-rich regions of the C-terminus . As such, PTTG increases the excretion of bFGF , which itself can increase ovarian cancer invasion ; therefore, PTTG itself may not directly induce tumorigenesis but acts indirectly on tissues expressing a higher level of bFGF, such as the ovary, fallopian tube, and cervix [36–38] to increase angiogenesis and stimulate expression of other activator genes, such as Ets-1 and urokinase-type plasminogen activator to promote tumor progression.
Since our incidence of tumor formation was ~17%, we cross-bred our TgPTTG mice with p53 mutant (p53+/−) mice with the assumption that p53+/− would enhance the incidence. Using this approach, TgPTTG/p53+/− animals resulted in earlier tumor development than PTTG or p53+/− alone (Figure 13) and increased the incidence of high grade leiomyosarcomas from 7% in p53+/− mice to 14% in TgPTTG/p53+/−. We also noted a significant incidence of cervical carcinomas of 63% in TgPTTG/p53+/−. Most cases of cervical cancer in women are due to human papilloma virus (HPV) infections that cause inactivation of p53 and Rb, mutations that mainly affect the squamous epithelium along the transformation zone as HPV infections require cells that are proliferating . In our TgPTTG mice, we noticed a reverse maturation of the basal squamous epithelium coupled to dysplasia. As PTTG increases cell proliferation as observed by PCNA staining, PTTG could serve to prime the basal epithelium, which could make these particular cells more susceptible to further neoplastic transformation due to alterations of additional genes, such as p53. We also noted teratocarcinomas in TgPTTG/p53−/−. While little is known about the genetic contributions to teratocarcinomas, the field theory states that normal germ cells that are placed in an environment that allows expression of the cancer phenotype have the potential to become cancerous . Constitutive overexpression of PTTG may alter the micro environment through enhanced secretion of growth factors, and thus allow normal cells to proliferate more rapidly causing transformation of normal cells to become tumorigenic leading to the formation of tumors, such as teratocarcinomas.
In our studies, we showed that PTTG is a functional oncogene that is capable of initiating transformation of normal tissue to dysplastic. Furthermore, a high expression level of PTTG was capable of inducing tumorigenesis in the ovary and other tissues leading to tumorigenesis. Coupling of TgPTTG with mutant p53 led us to conclude that the early neoplastic events (normal to dysplastic) were independent of p53 as the additional mutation did not enhance incidence of ovarian cancer; however overexpression of PTTG and loss of p53 function reduced the time of development of certain cancers, including sarcoma.
Alpha-subunit of glycoprotein hormone
Basic fibroblast growth factor
Friend Virus B-Type
Müllerian inhibitory substance type II receptor
Pituitary tumor transforming gene
- Rb+/− :
Heterozygous deletion of retinoblastoma
PTTG transgenic mice
Vascular endothelial growth factor.
The authors would like to thank Dr. Jason Chesney for his critical input and Dr. John Eaton for critical editing of the manuscript. Authors are also thankful to Penny White and Renu Kakar for their technical assistance. This work was supported by a grant from the National Institutes of Health, National Cancer Institute, CA124630 (SSK).
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