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[Cancer Research 61, 3262-3266, April 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Cytosine-Phosphoguanine Methylation of Estrogen Receptors in Endometrial Cancer

Masahiro Sasaki, Loulia Kotcherguina, Abhipsa Dharia, Seiichiro Fujimoto and Rajvir Dahiya1

Department of Urology, University of California San Francisco and VA Medical Center, San Francisco, California 94121 [M. S., L. K., A. D., R. D.], and Department of Obstetrics and Gynecology, School of Medicine, Hokkaido University, Kita-ku, Sapporo, Japan [M. S., S. F.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
We hypothesize that estrogen receptors (ERs) are differentially expressed in endometrial cancer. To test this hypothesis, we investigated the expression profile of ER{alpha} (ER{alpha}-A, ER{alpha}-B, ER{alpha}-C) and ERß genes and CpG methylation status in endometrial cancer cell lines and tissues using reverse transcription-PCR and methylation-specific PCR and direct DNA sequencing. The results demonstrated that ER{alpha}-A, ER{alpha}-B, and ERß were normally expressed whereas ER{alpha}-C gene was inactivated in all endometrial cancer cell lines. We further investigated the mechanisms of ER{alpha}-C gene inactivation through CpG methylation pathways. The treatment with demethylating agent (5'-aza-2'-deoxycytidine) restored ER{alpha}-C gene expression in all endometrial cancer cell lines. We further confirmed these findings with methylation-specific PCR and direct DNA sequencing and found that only ER{alpha}-C was methylated on all five different CpG sites in all cell lines. We further analyzed 88 cancerous and 46 normal endometrial tissues. The results demonstrated that only ER{alpha}-C was inactivated and methylated in 94% of cancer tissues. In 32 pairs of cancerous and normal endometrial tissues from the same patient, ER{alpha}-C was methylated in 29 of 32 cancer tissues but unmethylated in all normal endometrial tissues. This is the first report that demonstrates selective ER{alpha}-C gene inactivation through CpG methylation pathway in uterine endometrial cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Estrogens exert their effects through two ER2 types ({alpha} and ß) (1 , 2) . Three promoters, A, B, and C, have been identified for the human ER{alpha} gene (3 , 4) . These promoters regulate the synthesis of specific transcripts corresponding to ER{alpha}-A, ER{alpha}-B, and ER{alpha}-C isoforms. These ERs differ in various types of cells and tissues (3 , 4) . The expression levels of these ERs differ with respect to each other in certain target samples. The specific role of these ERs is unclear; however, the existence of elaborate mechanisms regulating their production suggests that each ER has a specific character. The ERs in specific cells may be critical for appropriate cellular response to estrogen. This specific pattern of ERs expression may enable estrogens to direct their effects to target tissues. Until now, there have been very few reports about mutation or other structural alterations of the ER genes in endometrial cancer (5 , 6) . One possible mechanism for changing the transcriptional status is methylation of CpG-enriched regions in this gene (7 , 8) . The ER genes contain CpG-enriched regions in the 5'-upstream region (9 , 10) . ER{alpha} gene methylation has been observed in several human cancers such as breast (11) , lung (12) , colorectal (13) , and hematopoietic neoplasm (14) and has been related to inactivation of ER gene expression (15) . However, the expression profile of ER{alpha} (ER{alpha}-A, ER{alpha}-B, ER{alpha}-C) and ERß and their CpG methylation status in endometrial cancer is lacking. This question is critical in understanding the complexity of ER gene expression and regulation in endometrial cancer cells. In this report, we analyzed the expression and methylation status of three ER{alpha} isoforms (ER{alpha}-A, ER{alpha}-B, and ER{alpha}-C) and ERß genes in endometrial cancer cell lines and tissues.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tissue Samples and Cell Lines.
Ishikawa, HHUA, HEC-IB, and MFE-296 endometrial cell lines were maintained in DMEM containing 10% FCS. The cells were treated with a freshly prepared solution of 5-aza-2'-deoxycytidine (Sigma Chemical Co., St. Louis, MO; Santa Cruz Biotechnology, Santa Cruz, CA). On day 1, a final concentration of 2 µg/ml 5-azaC in PBS was added to the flask. The next day, the medium was changed. On days 3 and 5, the cells were treated twice more as on day 1. On day 6, the cells were harvested (16) .

Primary endometrial tissues were obtained from the Department of Gynecology at the hospital of Hokkaido University, Japan. DNA was obtained from 88 cancer and 46 normal uterine endometrial samples. The histopathological types of the cancers were: 67 samples, endometrioid cancer; 2 samples, adenosquamous cancer; 5 samples, adenoacanthoma; 2 samples, clear cell cancer; and 12 samples, unknown type. In addition, we used 32 pairs of cancerous and normal endometrial samples from the same endometrial cancer patient.

RNA Isolation and RT-PCR.
Cells were washed and lysed with guanidine isothiocyanate solution. Total RNA was isolated by our previous method (16) . Three sets of primers, RT-A, RT-B, and RT-C, specifically amplify transcripts originating from promoters A, B, and C, respectively. A set of primers (RT-Common-f and RT-Common-r) amplifies transcripts common to these promoters. A set of primers (ERß-f and RT-ERß-r) specifically amplifies transcripts of ERß. Primers for ß-actin were chosen specifically to cross one intron in the ß-actin gene. In the presence of contaminating genomic DNA, additional larger bands would be amplified; the lack of amplification of the larger band was used as a control to rule out contamination with any genomic DNA. Negative controls without RNA and without reverse transcriptase were also performed.

DNA Extraction and Sodium Bisulfite Treatment.
DNA was isolated from the samples scraped from the paraffin-embedded sections. The microdissections were done from these samples as described previously (16) . DNA (~100 ng) was denatured using NaOH and treated with sodium bisulfite for 16 h (Introgen) as described previously (16) . Modified DNA was resuspended in 50 µl of Tris-EDTA and immediately stored at -20°C.

MSP and DNA Sequencing.
The primers and their PCR conditions are summarized in Table 1Citation and Fig. 1Citation . The fragment of DNA to be amplified was intentionally small for application of this technique to paraffin blocks, in which amplification of larger fragments is not possible. One primer set (U) will anneal to unmethylated DNA. A second primer set (M) will anneal to methylated DNA. The methods of PCR, electrophoresis, and gel visualization were described previously (16) . For confirmation of MSP, the PCR products were purified with a QIAquick PCR Purification Kit (Qiagen, Valencia, CA) and applied to direct DNA sequencing (16) .


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  		Table 1 Summary of the primer sets and PCR conditions for ER{alpha} and ERß

 


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  		Fig. 1. Structure of the upstream region of ER{alpha} and ERß genes. The genomic DNA ER types are schematically represented and three ER{alpha} promoters are shown in Fig. 1Citation . Bold black lines, positions and orientations for these MSP products; thin black lines, those of RT-PCR primers; {blacksquare}, specific regions to these isoforms in exon 1; lollipop signs, CpG sites.

 

   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Cell Lines.
MSP and RT-PCR were performed using these cell lines treated with and without demethylating reagent, 5-azaC (Table 2Citation , Fig. 2Citation ). By RT-PCR without 5-azaC treatment, no ER{alpha}-C expression were found, although ER{alpha}-A, ER{alpha}-B, and ERß expression was found in all of endometrial cancer cell lines examined (Fig. 2)Citation . By MSP, only ER{alpha}-C was methylated in all of the cell lines, whereas others were unmethylated. Treatment of cell lines with 5-azaC restored ER{alpha}-C expression in all of cancer cell lines (Table 2Citation , Fig. 2Citation ).


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  		Table 2 Expression profiles of ER in cell lines treated or not with 5-azaC

 


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  		Fig. 2. mRNA expression and methylation status of uterine endometrial cancer cell line, Ishikawa cell line, before and after treatment with the demethylating reagent, 5-azaC. A, mRNA expression. The RT-PCR of ER{alpha}-A, ER{alpha}-B, and ER{alpha}-C in uterine endometrial cancer cell line, Ishikawa: L, 100-bp ladder marker; U, unmethylated bands; M, methylated bands. Lanes 1–7, RT-PCR using cell line without 5-azaC; Lanes 8–14, ER{alpha}-A, ER{alpha}-B, ER{alpha}-C, and ERß gene expression in cell lines treated with 5-azaC. Lanes 1 and 8, expression of ER{alpha}-A; Lanes 2 and 9, expression of ER{alpha}-B; Lanes 3 and 10, expression of ER{alpha}-C; Lanes 4 and 11, ER{alpha} expression common to three isoforms; Lanes 5 and 12, expression of ERß; Lanes 6 and 13, ß-actin mRNA expression as positive controls; Lanes 7 and 14, negative controls. B, methylation status. Lanes 1–8, methylation-specific PCR using cell line without 5-azaC; 9–16, MSP using cell lines treated with 5-azaC. Lanes 1, 2, 9, and 10, unmethylated and methylated bands by ER{alpha}-A primers; Lanes 3, 4, 11, and 12, unmethylated and methylated bands by ER{alpha}-B primers. Lanes 5, 6, 13, and 14, unmethylated and methylated bands by ER{alpha}-C primers; Lanes 7, 8, 15, and 16, unmethylated and methylated bands by ERß primers.

 
Cancerous and Normal Endometrial Tissues.
All of the ERs were unmethylated in all 46 normal endometrial tissues (Table 3A)Citation . ER{alpha}-C was methylated in 83 of 88 cancer tissues (94%), whereas ER{alpha}-A, ER{alpha}-B, and ERß were unmethylated in all 88 cancerous tissues. A significant difference in the methylation status in ER{alpha}-C was found between cancerous and normal endometrial tissues (P < 0.001). Table 3, B and CCitation , shows the correlation of the methylation status of ER{alpha}-C, clinical stage, and pathological types of cancer tissues. All cancer tissues over stage 3 were methylated, whereas 5 of 58 cancer samples under stage 2 were unmethylated (P < 0.01).


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  		Table 3 Methylation status of ERs in cancer and normal tissues

 
Pairs of Cancerous and Normal Samples.
ER{alpha}-A, ER{alpha}-B, and ERß were unmethylated in all 32 pairs of cancerous and normal tissues. ER{alpha}-C was methylated in 29 of 32 cancer tissues (91%) and unmethylated in all 32 normal tissues (P < 0.001; Table 4Citation ). Fig. 3ACitation shows typical results of the MSP assay of these ER{alpha} isoforms and ERß in a pair of cancer and normal tissues from the same patient. Only the unmethylated bands of ER{alpha}-A, ER{alpha}-B, and ERß were observed in both cancerous and normal tissue (Lanes 1–8 and 13–16). There were only methylated ER{alpha}-C bands in cancerous tissues (Lanes 11 and 12), although only unmethylated ER{alpha}-C bands was observed in normal tissues (Lanes 9 and 10). Fig. 3BCitation shows the sequence data of ER{alpha}-C from these alleles. All CpG sites of ER{alpha}-C were methylated in endometrial cancer cell lines and cancerous tissues. All C are deaminated and converted to T of ER{alpha}-C in the normal tissue, whereas 5-methylcytosines remain unaltered in the cancer tissue, because it is methylated (Fig. 3B)Citation .


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  		Table 4 Properties of cancer tissues and normal tissues from the same patient

 


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  		Fig. 3. Methylation status of three ER{alpha} isoforms and ERß in cancerous and normal endometrium tissues: A, L, 100-bp ladder marker; U, unmethylated bands; M, methylated bands; N, normal tissues; C, cancerous tissues. Lanes 1–4, unmethylated and methylated ER{alpha}-A alleles; Lanes 5–8, unmethylated and methylated ER{alpha}-B alleles; Lanes 9–12, unmethylated and methylated ER{alpha}-C alleles; Lanes 13–16, unmethylated and methylated ERß alleles. B, examples of direct DNA sequencing chromatogram for ER{alpha}-C. CpG-methylated cytosines remained as cytosines, whereas unmethylated cytosines changed to thymidines in the PCR products. CpG sites are underlined, and all cytosines are deaminated and converted to thymines in normal tissue, whereas 5-methylcytosines remain unaltered in cancer tissue (*).

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
ER are implicated in the control of proliferation, differentiation, and development of uterine endometrial cells. The ERs are members of a closely related subgroup of nuclear receptors that includes the androgen, mineral corticoid, and glucocorticoid receptors (1 , 17) . Although ERs have three ER{alpha} isoforms and ERß genes, the biological significance of these isoforms and subtypes is unclear (2, 3, 4) . The discovery of three promoters in the ER{alpha} gene has previously led us to suggest that differential promoter usage could be one mechanism regulating expression of this steroid hormone receptor (4 , 17) .

In this study, we investigated the expression of three isoforms of ER{alpha} (ER{alpha}-A, ER{alpha}-B, and ER{alpha}-C) and ERß in endometrial cancer cell lines. We found that only the transcript from the distal promoter, ER{alpha}-C, is inactivated in human endometrial cancer cells, whereas both transcripts, ER{alpha}-A, and ER{alpha}-B, are present in endometrial cancer. We also investigated the mechanisms of inactivation of ER{alpha}-C gene through the analysis of CpG methylation using MSP and direct DNA sequencing. Only ER{alpha}-C is methylated in all human endometrial cancer cells, whereas other cells are unmethylated. The treatment of endometrial cancer cells with 5-azaC restored ER{alpha}-C expression in all ER{alpha}-C-negative cell lines. Our results clearly demonstrate that there is a tight relationship between the inactivation of ER{alpha}-C gene and CpG methylation of ER{alpha}-C. CpG-enriched regions are also found in other members of the hormone receptor super-family, including the androgen, progesterone, and ER genes (1 , 2) . We have recently observed hypermethylation of the ER{alpha}-A in prostate cancer during carcinogenesis (18) . We reported that hypermethylation of the ER{alpha}-A is associated with ER{alpha}-A inactivation in prostate cancer tissues and cultured prostate cancer cell lines (18) .

In this study, we also investigated the methylation status of various ERs in 88 cancerous and 46 normal endometrial tissues. ER{alpha}-A, ER{alpha}-B, and ERß were unmethylated in cancerous and normal samples. However, we found ER{alpha}-C hypermethylation in 94% of cancerous samples, whereas it was unmethylated in all 46 normal samples. We also found ER{alpha}-C methylation in 32 pairs of cancerous and normal endometrial tissues from the same patient. ER{alpha}-C was methylated in the 91% of cancer tissues, whereas it was unmethylated in all normal endometrial tissues.

ER are key components in the signal transduction pathways controlled by estrogen (1 , 2) . These pathways direct a variety of physiological processes, such as establishment and maintenance of female sex differentiation patterns, reproductive cycle and pregnancy, and embryonic and fetal development (1 , 4 , 17) . It is also well established that some of these pathways have influence in the carcinogenesis of several cancers (11, 12, 13, 14) . It is obvious that multiple promoter regions correspond to a variety of controls to the different tissues and cancers (4 , 17) . Other studies reveal that CpG islands in the 5'-region of the ER{alpha}-A and ER{alpha}-B are methylated in a significant fraction of primary human breast cancers (19 , 20) ; however, there is no information about ER{alpha} isoforms in endometrial cancer. This is the first report on extensive studies of ER and their isoforms in endometrial cancer. Inactivation of ER{alpha}-C gene through CpG methylation may be important in pathogenesis of endometrial cancer.


   FOOTNOTES
 
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.

1 To whom requests for reprints should be addressed, at Urology Research Center (112F), University of California San Francisco and VA Medical Center, 4150 Clement Street, San Francisco, CA 94121. Phone: (415) 750-6964; Fax: (415) 750-6639; E-mail: Urologylab{at}aol.com Back

2 The abbreviations used are: ER, estrogen receptor; 5-azaC, 5-aza-2'-deoxycytidine; MSP, methylation-specific PCR. Back

Received 12/ 4/00. Accepted 2/22/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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