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Clinical Cancer Research Vol. 12, 6373-6378, November 1, 2006
© 2006 American Association for Cancer Research

Human Cancer Biology

Overexpression of the Insulin-Like Growth Factor I Receptor and Activation of the AKT Pathway in Hyperplastic Endometrium

Adrienne S. McCampbell1, Russell R. Broaddus2, David S. Loose1 and Peter J.A. Davies1

Authors' Affiliations: 1 Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, Texas and 2 Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Peter J.A. Davies, Department of Integrative Biology and Pharmacology, University of Texas Houston Health Science Center, MSB 5.104, 6431 Fannin Street, Houston, TX 77030. Phone: 713-500-3082; Fax: 713-500-7455; E-mail: Peter.J.Davies{at}uth.tmc.edu.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Although there is considerable information on the molecular aberrations associated with endometrial cancer, very little is known of the changes in gene expression associated with endometrial hyperplasia.

Experimental Design: To address this, we have compared the level of expression of estrogen-regulated genes and components of the insulin-like growth factor I (IGF-I) signaling pathway in endometrial biopsies from subjects with normal endometrium, complex atypical endometrial hyperplasia, and endometrial adenocarcinoma (type I).

Results: There was a significant increase in the expression of the IGF-I receptor (IGF-IR) in biopsies from hyperplastic endometrium and endometrial carcinoma compared with the proliferative endometrium. The receptor was also activated, as judged by increased tyrosine phosphorylation. In addition, in endometrial hyperplasia and carcinoma, the downstream components of the IGF-IR pathway are activated, as reflected in increased Akt phosphorylation. Loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression in endometrial hyperplasia did not correlate with increased activation of IGF-IR. However, the simultaneous loss of PTEN expression and increased IGF-IR activation in hyperplasia was associated with an increased incidence of endometrial carcinoma.

Conclusions: These results suggest that up-regulation of IGF-IR and loss of PTEN may be independent events that give rise to complementary activation of the IGF-I pathway and increase the probability of the development of cancer. These studies suggest that increased expression of IGF-IR may be an important contributor to the risk of endometrial hyperplasia and cancer.

The clinicopathologic progression from normal endometrium to endometrial adenocarcinoma (EC) is thought to progress through an intermediary state of abnormal proliferation, complex atypical hyperplasia (CAH; ref. 1). The progression from CAH to EC has been estimated to occur in 23% of cases (2). Epidemiologic evidence suggests that in postmenopausal women, unopposed estrogen exposure, either endogenous or exogenous, is associated with an increased risk for the development of endometrial hyperplasia and endometrial adenocarcinoma, endometrioid type (3–6). Elevated serum estrogen levels as a result of obesity, polycystic ovarian disease, or ovarian tumors are associated with a 5-fold increased risk of EC (7–9). The molecular mechanism linking estrogen exposure and increased risk of development of CAH and EC has not yet been defined.

The action of estrogen is mediated through the estrogen receptors (ER{alpha} and ERß). Estrogen directly activates estrogen target gene transcription through the nuclear receptor (10). In the uterus, target genes whose transcription are regulated by estrogen include insulin-like growth factor I (IGF-I), progesterone receptor, and a number of transcription factors (11–13). The increased expression and activation of these intermediary molecules enhance the transcription of genes such as cyclin D1 that facilitate the entry of the cell into the cell cycle (14). Estrogen-induced increases in IGF-I expression result in the activation of the phosphoinositide-3-kinase pathway and Akt, thereby promoting cell survival through inhibition of downstream apoptotic pathways (15).

Cyclic changes in IGF-I expression and signaling play an important role in regulating the transition of the premenopausal endometrium through proliferative, secretory, and menstrual phases of the menstrual cycle (16, 17). The IGF's and their binding proteins, IGFBP's, regulate local endometrial differentiation and endometrial cyclic activity. Estrogen stimulates IGF-I gene expression in the uterus and has been shown to induce endometrial proliferation in mouse uterine epithelial cells (11, 18). IGF-I is produced in a cell cycle–dependent manner and increases in its transcription occur in the proliferative phase as compared with the secretory phase (17). The IGF-I pathway components are thought to regulate stromal-epithelial growth and differentiation in both an autocrine and paracrine manner (11).

The effects of IGF-I on endometrial cell proliferation are mediated by the activation of the IGF-I receptor (IGF-IR), a tyrosine kinase receptor that signals via the activation of the phosphoinositide-3-kinase/Akt pathway (11). IGF-IR is localized to the luminal and glandular epithelium as well as the stroma, and its expression is down-regulated by progesterone (19, 20). In endometrial cells, the activity of the phosphoinositide-3-kinase/Akt pathway is also critically regulated by the activity of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a lipid phosphatase that negatively regulates phosphoinositide-3-kinase activity by the dephosphorylation of phosphoinositol(3,4,5) triphosphate (21). PTEN activity has been found to be suppressed in 55% of CAH, and in up to 83% of EC (22). Decreased PTEN expression has been proposed to facilitate an increase in the activation of Akt, thereby stimulating survival signaling in the endometrium and contributing to the development of CAH and EC (22). However, the molecular link between estrogenization of the endometrium and changes in PTEN expression are not well understood.

In order to gain further insight into the role of estrogen and the IGF-I pathway in the development of CAH and carcinoma, we investigated the expression and activation of estrogen-responsive genes and IGF-I pathway components. Surprisingly, our results provide evidence that the endometrium of postmenopausal women with CAH is not highly "estrogenized", as indicated by the lack of significant change in the expression of estrogen-responsive genes. We have, however, identified overexpression and activation of IGF-IR independent of changes in PTEN expression in CAH.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Endometrial tissue samples. Formalin-fixed, paraffin-embedded sections of human endometrial biopsies were obtained from the Department of Pathology, University of Texas M.D. Anderson Cancer Center (Houston, TX) from 10 women with proliferative phase endometrium, 7 women with secretory phase endometrium, and 17 postmenopausal women with endometrial CAH. Proliferative and secretory phase tissues were obtained from premenopausal women who underwent biopsy for the clinical evaluation of abnormal vaginal bleeding. Formalin-fixed, paraffin-embedded sections of endometrial endometrioid adenocarcinoma grade 1 (EEC grade 1, n = 27) were derived from hysterectomy surgical specimens submitted to the Department of Pathology, University of Texas M.D. Anderson Cancer Center. H&E-stained slides were microscopically evaluated by a gynecologic pathologist (R.R. Broaddus) to confirm the diagnosis. For the CAH and EEC grade 1 samples, H&E-stained slides were microscopically reviewed to ensure the lack of contaminating normal endometrium. Cases with contaminating normal endometrium were not used.

Patient characteristics. Height and weight information for each patient was obtained from the medical record and was used to calculate patient basal metabolic index (BMI) using the formula, BMI = [weight (kg) / height (cm)2] x 104. A BMI of ≥30 kg/m2 was categorized as obese (23). Patient characteristics including age, BMI, and findings at hysterectomy are listed in Table 1 .


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  		Table 1. Patient characteristics

 
RNA isolation. Five 10-µmol/L sections were cut from the paraffin-embedded blocks using a T35 microtome (Microm, Walldorf, Germany). Tissue sections were deparaffinized using two xylene washes. RNA was extracted using the MasterPure Reagent Kit (Epicenter, Madison WI). Proteinase K digestion was done for 4 hours at 65°C in a SDS-containing lysis solution followed by isopropanol precipitation and two ethanol washes. DNA was digested by incubation with RNase-free DNase I with RNase Inhibitor for 15 minutes at 37°C. DNase I was heat-inactivated at 75°C for 10 minutes.

Reverse transcription and quantitative real-time PCR. Reverse transcription and quantitative real-time PCR were done as previously described (24). The sequences of forward and reverse primers and TaqMan probes for each specific assay are listed in Table 2 .


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  		Table 2. Quantitative real-time PCR primer/probe sequences

 
Immunohistochemistry. Immunohistochemistry was done for a subset of the formalin-fixed, paraffin-embedded biopsies used for real-time PCR transcript analysis, from proliferative phase endometrium (n = 6), endometrial CAH (n = 14), and EEC grade 1 (n = 18). Tissue sections were deparaffinized and endogenous peroxidases were quenched by incubation in 1% H2O2. Antigen retrieval was done by microwave in 10 mmol/L citrate buffer (pH 6.0). Slides were incubated with primary antibody (1:50) in PBS containing 10% normal serum overnight at 4°C. Primary antibodies were specific to phosphorylated (Tyr1131) IGF-IR, or the {alpha}-subunit of the IGF-IR, or phosphorylated (Ser473) Akt or total Akt (all from Cell Signaling Technology, Beverly, MA), or PTEN (clone 6H2.1; Cascade Biosciences, Winchester, MA). A biotin-labeled secondary antibody was conjugated for 30 minutes at 37°C. Sections were stained using avidin-biotinylated horseradish peroxidase complex from the Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA) according to the manufacturer's instructions. Diaminobenzidine reagent (Vector Laboratories) was incubated with sections to visualize peroxidases for up to 30 minutes. Sections were counterstained with hematoxylin or methyl green, dehydrated, and mounted. Controls that lacked primary antibody were incubated in 1x PBS with 10% normal serum in each experiment. Controls that contained the corresponding blocking peptide in combination with the primary antibody were done for each experiment. Immunostained sections were examined by light microscopy and evaluated and scored semiquantitatively according to the intensity of staining on a scale of 0 (no staining) to 3+ (strong staining). Tissues with 2+ or 3+ staining in >10% of cells were considered positive for protein expression.

Statistical analyses. Significant differences in population means were calculated by unpaired Student's t tests, ANOVA, or nonparametric Mann-Whitney test. {chi}2 test was used to evaluate the frequency of immunostaining by group. Any correlations were evaluated by Pearson correlation analysis and confirmed by Spearman's and Kendal's tests. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Expression of estrogen-regulated genes in normal proliferative endometrium and CAH. Epidemiologic studies link estrogen exposure to the development of endometrial CAH and carcinoma (3, 4). We therefore measured the level of transcript expression of the estrogen receptor {alpha} and a panel of genes well-known to be regulated by estrogen, including progesterone receptor, cyclin D1, and IGF-I, using quantitative real-time PCR in formalin-fixed, paraffin-embedded biopsies from proliferative endometrium and CAH (Table 3 ). The transcript levels of estrogen receptor {alpha} were not significantly different between the proliferative phase and CAH. Similarly, there was no significant difference in the levels of transcripts of the estrogen-regulated genes, progesterone receptor, IGF-I, or cyclin D1. The lack of difference between the expression of estrogen-regulated genes in CAH and proliferative endometrium suggests that the abnormal proliferative state of CAH is not due to excessive chronic estrogenization of the endometrium.


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  		Table 3. Levels of transcripts from proliferative phase endometrium and endometrial hyperplasia (CAH)

 
IGF-I pathway transcripts. Because of the critical role of IGF-I in regulating the proliferation of the normal endometrium, we evaluated the level of transcript expression of the IGF-I pathway components (IGF-I, IGF-II, IGF-IR, IGFBP-3, and IGFBP-5) in proliferative endometrium and CAH (Table 3). There was no significant difference in the expression of IGF-I, IGF-II, IGFBP-3, or IGFBP-5 transcript levels. However, the IGF-IR transcript level was ~6-fold higher in CAH compared with the proliferative endometrium (P < 0.001). Figure 1 shows the individual transcript levels of IGF-IR for endometrial biopsies of proliferative or secretory phase endometrium, CAH, and EEC grade 1. IGF-IR transcripts were significantly elevated in both CAH and EEC grade 1 compared with normal endometrium.


Figure 1
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  		Fig. 1. IGF-IR transcript levels in individual endometrial samples. The levels of IGF-IR transcript were measured by quantitative real-time PCR in formalin-fixed paraffin-embedded proliferative (n = 10) and secretory (n = 7) phase endometria, endometrial CAH (n = 17), and grade 1 endometrioid carcinoma (n = 27). The values of IGF-IR transcript molecules were normalized to the 18S rRNA. Bars, mean population values.

 
IGF-IR expression and phosphorylation in the proliferative endometrium, CAH, and EEC grade 1. In order to evaluate whether the increase in IGF-IR transcript levels resulted in increased expression of the IGF-IR protein, we assessed IGF-IR immunohistochemically (Fig. 2 ). There was a low level (1+) of IGF-IR expression in the cytosol of the stroma and glandular epithelium of all (6 of 6) of the proliferative endometria (Fig. 2A). However, IGF-IR expression was high (3+) in the cytosol of the glandular epithelium in the majority (5 of 6) of CAH and all (18 of 18) of the carcinomas (Fig. 2B and C). Although the IGF-IR expression was increased in both stromal and epithelial cells, the level of expression was highest in the epithelial cells.


Figure 2
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  		Fig. 2. Immunostaining for IGF-IR, phosphorylated IGF-IR, Akt and phosphorylated Akt in the endometrium. IGF-IR immunoreactivity in the proliferative endometrium (A), CAH (B), and EEC grade 1 (C). Phospho-IGF-IR immunoreactivity in the proliferative endometrium (D), CAH (E), and EEC grade 1 (F). Akt immunoreactivity in the proliferative endometrium (G), CAH (H), and EEC grade 1 (I). Phospho-Akt immunoreactivity in the proliferative phase (J), CAH (K), and EEC grade 1 (L). Inset, the appropriate peptide blocked controls for the individual antibodies.

 
Increased expression of IGF-IR might or might not result in activation of the IGF-I signaling pathway. To determine whether the receptor is activated, we measured tyrosine phosphorylation (P-Tyr1131) of the activation domain of the IGF-IR in biopsies from the proliferative endometrium, CAH, and EEC grade 1 (Table 4 ; Fig. 2). IGF-I and IGF-II activate the IGF-IR by triggering autophosphorylation of a triple tyrosine cluster within the kinase domain (25). The level of IGF-IR phosphorylation was undetectable (0) in all (6 of 6) of the proliferative endometria (Fig. 2D). The phosphorylation of the IGF-IR was uniformly increased in the majority (12 of 14) of CAH. Phosphorylated IGF-IR was present in the cytosol of both the glandular epithelium and stroma of CAH and the majority (14 of 18) of EEC grade 1 (Table 4; Fig. 2E and F). In summary, there is a consistent pattern of increased expression and activation of the IGF-IR in endometrial CAH as compared with the proliferative endometrium.


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  		Table 4. Immunohistochemical expression of IGF-IR, phosphorylated IGF-IR, Akt, phosphorylated Akt, and PTEN in the proliferative phase endometrium, CAH, and EEC grade 1

 
Phosphorylation of Akt. Signaling through the IGF-IR can lead to phosphorylation of Akt. In order to evaluate the degree of downstream activation of the IGF-I signaling pathway, we examined the immunohistochemical expression of Akt and its activation by phosphorylation of Ser473 (Table 4; Fig. 2). The level of Akt was much higher in EEC grade 1; however, Akt expression was similar in the proliferative endometrium and CAH. Akt expression was high (3+) in the cytosol of all (18 of 18) of the carcinomas (Fig. 2I). The expression of Akt was moderate (2+) in the cytosol of the stroma and glandular epithelium of the proliferative endometrium (5 of 6) and CAH (6 of 6; Fig. 2G and H). The level of Akt phosphorylation was high in CAH and EEC grade 1 as compared with a very low level of expression in the proliferative endometrium. The level of phosphorylation of Akt was high (3+) in the cytosol of the glandular epithelium and stromal cells of the majority (13 of 14) of CAH and the majority (16 of 18) of EEC grade 1 (Fig. 2K and L). The level of phosphorylation of Akt was undetectable (0) in all (6 of 6) of the proliferative endometria (Fig. 2J). Our results suggest that Akt is activated in a majority of CAH and grade 1 carcinoma. In summary, both overexpression of IGF-IR and downstream activation of Akt are present in endometrial hyperplasia and carcinoma.

PTEN expression. The lipid phosphatase PTEN is a negative regulator of the IGF-I/Akt signaling pathway (21). Loss of PTEN expression due to mutation is very common in CAH and EC (22). In order to determine if loss of PTEN was correlated with the activation of IGF-IR and Akt, we evaluated the pattern of protein expression of PTEN in CAH and EEC grade 1 previously used to characterize the expression of IGF-IR and Akt (Table 4; Fig. 3 ). The loss of expression of PTEN in the cytosol of the glandular epithelium of multiple glands occurred in the majority (9 of 14) of CAH (Fig. 3B). Loss of expression of PTEN occurred in all (18 of 18) endometrial carcinomas (Fig. 3C). Overall, there was no correlation between the loss of PTEN expression and activation of IGF-IR in CAH (Pearson's correlation, 0.41; P < 0.20) and EEC grade 1 (Pearson's correlation, 0.00; P < 1.0), suggesting that these two events are independent of each other.


Figure 3
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  		Fig. 3. PTEN immunoreactivity in hyperplastic endometrium with intact expression of PTEN (A), hyperplastic endometrium with loss of PTEN expression (B), and EEC grade 1 with loss of PTEN expression (C). B and C, PTEN expression is retained in the nonneoplastic stromal cells, but not in the glandular epithelial cells.

 
Evaluation of IGF-IR activation status and PTEN expression status in CAH associated with EC. For the 14 patients with CAH biopsies in which we evaluated IGF-IR activation and PTEN expression, 10 ultimately had hysterectomies at M.D. Anderson Cancer Center. Five of these had EEC grade 1 arising in association with CAH, whereas five had CAH only. Although our sample size is limited, the majority (5 of 6) of endometrial CAH with activated IGF-IR and loss of PTEN expression ultimately had EEC grade 1 in the uterus at hysterectomy (Fig. 4 ). This was very similar to the profile of EEC grade 1 tumors, in which concurrent activated IGF-IR and PTEN loss of expression was present in the majority (14 of 18) of cases (Fig. 4). These results suggest that, in endometrial CAH, concurrent loss of PTEN expression and activation of the IGF-IR may be associated with a higher risk of either concurrent endometrial carcinoma or the development of carcinoma.


Figure 4
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  		Fig. 4. IGF-IR activation status and PTEN expression status in (A) CAH without associated endometrial cancer (EEC gr1; n = 5), (B) CAH with associated endometrial cancer (EEC gr1; n = 5), or (C) endometrial cancer tumors (n = 18). Patients with an initial biopsy diagnosis of complex atypical endometrial hyperplasia were subsequently treated with hysterectomy. The entire endometrium was then microscopically examined by a gynecologic pathologist to determine the presence of endometrial carcinoma in the uterus. Endometrial hyperplasia biopsies for which IGF-IR and PTEN immunoreactivity were determined, were segregated according to the absence (n = 5; A) or presence (n = 5; B) of endometrial carcinoma in the hysterectomy specimen. A separate set of EEC grade 1 cases (n = 18; C) was also examined for comparison. Statistical significance was not determined due to the small sample size.

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
There is a great deal of evidence that the IGF-I pathway plays an important role in normal endometrial proliferation. In premenopausal or normal cycling endometrium, increased IGF-I has been implicated in normal proliferation of the glandular epithelium and stromal cells (16, 19). The IGF-I signaling pathway can also be activated by decreased levels of PTEN expression because PTEN is a phosphatase that normally suppresses the activity of the phosphoinositide-3-kinase pathway (21, 26). In our analysis of endometrial CAH, we did not find evidence of increased IGF-I, but we did find marked up-regulation of IGF-IR (Fig. 1) and phosphorylation of IGF-IR (Fig. 2E). The intensity of immunohistochemical staining of IGF-IR in CAH is comparable to that of EEC grade 1 (Fig. 2B and C).

Increased expression of IGF-IR has been reported in cancers of the colon, prostate, and breast, often in association with an increased expression of IGF-I or IGF-II (27–31). Increased expression of IGF-IR has been identified to be an early event in colon and prostate cancer progression, occurring in the corresponding premalignant lesions. Overexpression of IGF-IR protein has been reported in prostatic intraepithelial neoplasia and colonic adenoma; accompanied by an increase in IGF-I or IGF-II expression (31–33). For endometrial CAH and EEC grade 1, it seems that only the receptor is increased. This is one of the few reports of increased IGF-IR expression in a premalignant condition, and is the only report of increased activation, as measured by phosphorylation of IGF-IR.

We do not know the molecular factors that account for the up-regulation of the expression of IGF-IR. Estrogen itself does not increase IGF-IR gene expression (34). IGF-IR is a target of transcriptional regulation by Akt (35). Tanno et al. identified that Akt activation up-regulates protein expression of the IGF-IR in human pancreatic cell lines, PANC-1 and AsPC-1. In addition, AKT inhibition by PTEN suppressed the expression of IGF-IR (35). This presents the possibility of a feed forward loop, in which loss of PTEN expression due to mutation and the overexpression of IGF-IR may be driven by activated Akt. Our studies indicate that the global activation of IGF-IR is associated with the activation of Akt independent of the focal loss of PTEN. This presents the possibility that in endometrial CAH, IGF-IR activation may precede PTEN loss in the molecular hierarchy of events.

Recent studies have shown that the distinction between CAH and EEC grade 1 can be quite difficult following the microscopic examination of an endometrial biopsy (36). Furthermore, the rate of concurrent EC at the time of hysterectomy in patients with a biopsy diagnosis of CAH is quite high (42.6%; ref. 37). These issues are important, as many premenopausal women with a biopsy diagnosis of hyperplasia are reluctant to consent to hysterectomy, and may seek hormonal therapy with high dose progestins instead. Therefore, molecular markers of cancer risk in endometrial biopsies with hyperplasia would be useful at the clinical level. Unfortunately, such molecular markers do not exist at this time. In the present study, we found that CAH biopsy cases in which there was both loss of PTEN, and increased levels of IGF-IR, were associated with the presence of EEC grade 1 in the subsequent hysterectomy specimen (Fig. 4). The majority (14 of 18, 78%) of the EEC grade 1 cases examined in the present study showed a concurrent profile of PTEN loss and elevated activated IGF-IR. Although the numbers in the present study are small, a prospective study in which PTEN and IGF-IR are assessed in endometrial biopsies with CAH would be helpful in determining if these markers are predictive of concurrent/subsequent development of endometrial carcinoma in the hysterectomy specimen. Pharmacologic suppression of IGF-I signaling by small molecule inhibitors or monoclonal antibodies to the IGF-IR, may be a good target for the prevention of endometrial cancer (38–41).


   Footnotes
 
Grant support: NIH Uterine Cancer Specialized Programs of Research Excellence (1P50CA098258-01).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/14/06; revised 6/22/06; accepted 7/ 6/06.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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Commentary

Is the Type I Insulin-Like Growth Factor Receptor a Therapeutic Target in Endometrial Cancer?
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Clin. Cancer Res. 2006 12: 6323-6325. [Full Text] [PDF]



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