The expression of ER, PR in endometrial cancer and analysis of their correlation with ERK signaling pathway

Lan Luo; Lina Xu; Liang Tang

doi:10.3233/CBM-170457

. 2017 Dec 12;21(1):145–149. doi: 10.3233/CBM-170457

The expression of ER, PR in endometrial cancer and analysis of their correlation with ERK signaling pathway

Lan Luo ^a, Lina Xu ^a, Liang Tang ^b

PMCID: PMC13075739 PMID: 29081408

Abstract

Endometrial carcinoma (EC) is a common malignant tumor in gynecology. Its incidence and development are closely associated with the levels of estrogenic and progesterone hormone. Extracellular signal-regulated kinase (ERK) signaling pathway abnormity is associated with a variety of tumors. This study detected estrogen receptor (ER), progesterone receptor (PR), ERK1, and ERK2 expression in EC and analyzed their correlations. A total of 40 EC patients in our hospital were selected as test group, while another 40 healthy volunteers were enrolled as control group. ER, PR, ERK1, and ERK2 expression in EC tissue, para-carcinoma tissue, and normal endometrial tissue were detected by immunohistochemistry and Western blot. The positive rate of ER, PR, ERK1, and ERK2 in the test group was 50%, 40%, 60%, and 65%, respectively, which were significantly higher than those in the control ( $P<$ 0.05). ER, PR, ERK1, and ERK2 protein expressions in EC cell were significantly higher than those in the control ( $P<$ 0.05). ERK1 and ERK2 presented positive correlation with ER and PR ( $P<$ 0.05). In conclusion, EC patients presented higher expressions of ER, PR, which were correlated with higher levels of ERK1 and ERK2, suggesting they might be involved in the pathogenesis of EC.

Keywords: Endometrial carcinoma, ER, PR, ERK1, ERK2

1. Introduction

The incidence and development process of malignant tumor involves multiple genes. A variety of signaling pathways regulate the different stages synergistically. One of the transductions abnormity may cause importantly physiological and pathological chang-es [1, 2, 3]. MAPK signaling pathway is found to play a critical role in the process of tumor cell proliferation, of which the extracellular signal-regulated kinase (ERK) presents the dominant role [4]. Estrogen and progestogen are important hormones in regulating endocrine. Their imbalance can affect the normal state. Endometrial carcinoma (EC) is characterized as hormone-dependence. Long-term high level of estrogen and low level of progestogen may stimulate endometrial hyperplasia, further leading to the development of EC. Estrogen can bind to estrogen receptor (ER), which is located in the nucleus, while progestogen can bind to progestogen receptor (PR). It was reported that ER and PR might be used to evaluate the degree of endometrial malignant hyperplasia. The abnormal levels of ER and PR can lead to the incidence and development of EC [5]. This study tested the expression levels of ER, PR, and ERK in EC patients and analyzed their correlations.

2. Materials and methods

2.1. General information

A total of 40 EC patients in the First People’s Hospital of Jining City were selected as test group with a mean age of 41.2 $\pm$ 3.5 years old. The pathologic type was aggressive, serous and well-differentiated carcinoma with high grade. They were diagnosed by pathology and received surgical resection. The tissues were collected immediately at the operating theater from the removed uterus. The paracarcinoma tissue which was located at 2 cm away from the tumor tissue was also extracted. Another 40 healthy volunteers who underwent heathy examinations in our hospital were enrolled as control with a mean age of 45.3 $\pm$ 3.1 years old. The control samples were collected at operating theater using pipelle.

Inclusion criteria: Menstrual rule; no use of hormonal drugs within three months; no other ovary or uterus benign and malignant lesions; No serious liver and kidney disease.

Exclusion criteria: Endometrial hyperplasia; corpus uteri or cervical inflammation; long-term use of hormone drugs; other gynecological malignant tumors.

This study has been pre-approved by the ethical committee of the First People’s Hospital of Jining City. All subjects have signed the consent forms before recruitment in this study.

2.2. Reagents and instruments

ER, PR, ERK1, and ERK2 blocking buffer and rabbit anti mouse secondary antibody were purchased from Keygentec. ER, PR, ERK1, and ERK2 monoclonal antibodies were from Cell Signaling. Anti rabbit IgG-HRP was from Bioworld. Centrifugal machine was from Shanghai Flying Pigeon. Microplate reader was from TECNA. Image analysis system was from Hewlett Packard.

2.3. Immunohistochemistry

The specimen was fixed and embedded before being sectioned at 3 $\mu$ m thickness. The wax sheet was then put on the glass slide at 60 ${{}^{\circ}}$ C overnight. After treated with xylene and ethanol, the specimen was boiled in the pressure cooker. Next, the specimen was treated with hydrogen peroxide and blocking buffer. After incubated with primary antibody for 1 h, diluted secondary antibody was added into the specimen and incubated for 10 min. At last, the slice was developed by DAB.

Analysis: Brown granules appeared on cell membrane, cytoplasm, or nucleus were considered as positive. For the slice, negative (-) was defined as $\leqslant$ 10%; weak positive (+) as 11%-25%; positive (++) as 26%–50%; strong positive (+++) as $>$ 50%.

2.4. Endometrial cell isolation

The endometrial tissue was cut into pieces under aseptic condition and put into the solution containing penicillin and streptomycin. After washed and digested, the cells were resuspended in DMEM with a number of 10 ${}^{4}$ cells/ml and passaged at 1:2. The cells were observed under the microscope sand counted.

2.5. Western blot

A total of 40 $\mu$ g protein was separated by SDS-PAGE and transferred to membrane. After blocked at room temperature, the membrane was incubated with primary antibody (1:200 dilutions, $\beta$ -actin 1:500) at room temperature for 30 min and then incubated with secondary antibody (1:2000) for 1 h. At last, the membrane was developed for analysis.

2.6. Statistical analysis

The statistical analysis was performed on SPSS17.0 software. The data was depicted as mean $\pm$ standard deviation. Enumeration data was compared by chi-square test, while measurement data was compared by ANOVA with two-sided. $P<$ 0.05 was considered as statistical significance.

3. Results

3.1. ER and PR expression in endometrial tissue from patients detected by immunohistochemistry

The positive rate of ER and PR in the test group was 50% and 40%, respectively. They were significantly higher than those in the paracarcinoma tissue and control ( $P<$ 0.05) (Table 1, Fig. 1).

Table 1.

ER and PR expression in endometrial tissue

Group	Cases	ER				PR
		–	+-++	+++	Positive rate (%)	–	+-++	+++	Positive rate (%)
Test group	40	20	14	6	50*	24	13	3	40#
Paracarcinoma tissue	40	26	4	0	10	26	4	0	10
Control	40	28	2	0	5	28	2	0	5

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${}^{*}P=$ 0.0031, compared with paracarcinoma tissue. # $P=$ 0.014, compared with control.

Figure 1. — ER and PR expression in endometrial tissue ( $\times$ 400). A: ER (+++) in cancer tissue; B: ER (+) in paracarcinoma tissue; C: ER (-) in control; D: PR (+++) in cancer tissue E: PR (++) in paracarcinoma tissue F: PR (-) in control.

3.2. ERK1 and ERK2 expression in endometrial tissue from patients detected by immunohistochemistry

The positive rate of ERK1 and ERK2 in the test group was 60% and 65%, respectively. They were significantly higher than those in the paracarcinoma tissue and control ( $P<$ 0.05) (Table 2, Fig. 2).

Table 2.

ERK1 and ERK2 expression in endometrial tissue

Group	Cases	ERK1				ERK2
		-	+-++	+++	Positive rate (%)	-	+-++	+++	Positive rate (%)
Test group	40	16	14	10	60*	14	16	10	65#
Paracarcinoma tissue	40	22	7	1	20	22	8	0	20
Control	40	26	4	0	10	26	4	0	10

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${}^{*}P=$ 0.021, compared with paracarcinoma tissue. # $P=$ 0.006, compared with control.

Figure 2. — ERK1 and ERK2 expression in endometrial tissue ( $\times$ 400). A: ERK1 (+++) in cancer tissue; B: ERK1 (+) in paracarcinoma tissue C: ERK1 (-) in controll; D: ERK2 (+++) in cancer tissue; E: ERK2 (++) in paracarcinoma tissue F: ERK2 (-) in control.

3.3. ER, PR, ERK1, and ERK2 protein expression in endometrial cells

Western blot was applied to test ER, PR, ERK1, and ERK2 protein expressions in endometrial cells. It was found that their levels in test group weree markedly higher than those in the control ( $P<$ 0.05) (Table 3, Fig. 3).

Table 3.

ER, PR, ERK1, and ERK2 protein expression in endometrial cells

Group	ER	PR	ERK1	ERK2
Test	13.54 $\pm$ 2.05*	8.24 $\pm$ 4.98*	9.53 $\pm$ 6.43*	11.53 $\pm$ 6.43*
	( $P=$ 0.042)	( $P=$ 0.002)	( $P=$ 0.029)	( $P=$ 0.009)
Control	1.08 $\pm$ 0.07	1.02 $\pm$ 0.09	1.04 $\pm$ 1.12	1.03 $\pm$ 1.01

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${}^{*}P<$ 0.05, compared with control.

Figure 3. — ER, PR, ERK1, and ERK2 protein expression in endometrial cells.

3.4. The relationship of ERK1 expression with ER and PR in endometrial carcinoma cells

The relationship of ERK1 expression with ER and PR in endometrial carcinoma cells was also analyzed. The positive rate of ERK1 was lower in ER negative EC patients, while it was higher in ER positive EC patients. ERK1 showed a positive correlation with ER ( $r=$ 0.859, $P=$ 0.002). The positive rate of ERK1 was lower in PR negative EC patients, whereas it was higher in PR positive EC patients. ERK1 showed a positive correlation with ER ( $r=$ 0.723, $P=$ 0.017) (Table 4).

Table 4.

The relationship of ERK1 expression with ER and PR

Group	Cases	ERK1
		–	+
ER(-)	20	10	6
ER(+)	20	6	18
PR(-)	24	8	10
PR(+)	16	8	14

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3.5. The relationship of ERK2 expression with ER and PR in endometrial carcinoma cells

The relationship of ERK2 expression with ER and PR in endometrial carcinoma cells was analyzed. The positive rate of ERK2 was lower in ER negative EC patients, while it was higher in ER positive EC patients. ERK2 exhibited a positive correlation with ER ( $r=$ 0.882, $P=$ 0.001). The positive rate of ERK2 was lower in PR negative EC patients, whereas it was higher in PR positive EC patients. ERK2 presented a positive correlation with ER ( $r=$ 0.633, $P=$ 0.014) (Table 5).

Table 5.

The relationship of ERK2 expression with ER and PR

Group	Cases	ERK2
		–	+
ER(-)	20	9	6
ER(+)	20	5	20
PR(-)	24	10	12
PR(+)	16	4	14

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4. Discussion

EC is a common female malignant tumor with younger trend and increasing incidence. As one of the most women malignant tumors only after breast cancer, it seriously impairs women’s health. There are numerous prognosis factors, including clinical stage, vascular involvement, interstitial infiltration, and histological grading. Following the development of molecular biological technology, malignant tumor related factors were gradually identified. It was considered that some abnormal factors, such as oncogene activation and tumor suppressor gene inactivation, can block the signaling transduction [6, 7]. ERK signaling pathway can be activated by a variety of extracellular factors, such as growth factors and transcription factors, to regulate cell growth [8, 9]. This study selected EC patients in our hospital to detect ER, PR, ERK1, and ERK2 expression levels and analyze their correlation.

It was found that ER and PR were highly expressed in EC tissues. Furthermore, the positive rate of ERK1 and ERK2 reached 60% and 65%, respectively, which was significantly higher than those in paracarcinoma tissue and control. It suggested that ERK1 and ERK2 were highly expressed in EC tissue. Moreover, it was showed that ER, PR, ERK1, and ERK2 protein expressions in the EC cells were also significantly upregulated. ER belongs to a nuclear hormone receptor family, while PR belongs to a steroid hormone receptor family [10, 11]. They can regulate EC development. Hormone has the role of stimulating intimal hyperplasia. Low level of the hormone stimulation may increase the activity of glands in atrophic intima, leading to promotion of EC incidence and development [12]. ERK1 and ERK2 signaling pathways have been found to be activated in multiple malignant tumors, such as lung cancer and breast cancer [13]. Yasunari demonstrated that ERK1 and ERK2 were excessively activated in EC independent of KRAS and BRAF, and can affect the prognosis [14, 15].

This study further revealed that ERK1 and ERK2 were positively correlated with ER and PR. It was reported that estrogen participated in mediating ERK activation in a variety of malignant tumors, such as astrocytoma and osteoblastoma [16]. Previous study transfected ER to Hela cells and found ER can activate ERK signaling pathway. The level of estrogen may impact ERK signaling pathway [17]. It was demonstrated that estrogen elevation in breast cancer can stimulate cancer cells proliferation [18]. More than that, as an important signaling pathway in the body, ERK may stimulate cancer cells proliferation that is closely associated with estrogen level in the microenvironment [18, 19, 20]. ERK plays an important role in the regulation of EC incidence and development.

5. Conclusion

ER, PR, ERK1, and ERK2 were highly expressed in EC patients. ERK1 and ERK2 were positively correlated with ER and PR. Interactions among ER, PR ERK1 and ERK2 might participate in EC incidence and development. However, whether ER and PR regulate ERK1 and ERK2 in EC remains unclear and requires in-depth investigation, which may provide new orientation for EC prognosis and treatment.

Conflict of interest

The authors have no conflict of interest to report.

References

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[ref001] [1]. Yu C.G., Jiang X.Y., Li B., Gan L. and Huang J.F., Expression of ER, PR, C-erbB-2 and Ki-67 in Endometrial Carcinoma and their Relationships with the Clinicopathological Features, Asian Pac J Cancer Prev 16 (2015), 6789–6794. [DOI] [PubMed] [Google Scholar]

[ref002] [2]. Gao J., Tian J., Lv Y., Shi F., Kong F., Shi H. and Zhao L., Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells, Cancer Sci 100 (2009), 389–395. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref003] [3]. Li Y., Jia Y., Che Q., Zhou Q., Wang K. and Wan X.P., AMF/PGI-mediated tumorigenesis through MAPK-ERK signaling in endometrial carcinoma, Oncotarget 6 (2015), 26373–26387. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref004] [4]. Kim T.H., Yoo J.Y., Kim H.I., Gilbert J., Ku B.J., Li J., Mills G.B., Broaddus R.R., Lydon J.P., Lim J.M., Yoon H.G. and Jeong J.W., Mig-6 suppresses endometrial cancer associated with Pten deficiency and ERK activation, Cancer Res 74 (2014), 7371–7382. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref005] [5]. Scarpin K.M., Graham J.D., Mote P.A. and Clarke C.L., Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expr ession, nuclear positioning and coregulator expression, Nucl Recept Signal 7 (2009), e009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref006] [6]. Bartosch C., Monteiro-Reis S., Vieira R, Pereira A, Rodrigues M, Jeronimo C, Lopes JM. Endometrial Endometrioid Carcinoma Metastases Show Decreased ER-Alpha and PR-A Expression Compared to Matched Primary Tumors. PLoS One 10 (2015), e0134969. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref007] [7]. Markowska A., Pawalowska M., Filas V., Korski K., Grybos M., Sajdak S., Olejek A., Bednarek W., Spiewankiewicz B., Lubin J. and Markowska J., Does Metformin affect ER, PR, IGF-1R, beta-catenin and PAX-2 expression in women with diabetes mellitus and endometrial cancer? Diabetol Metab Syndr 5 (2013), 76. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref008] [8]. Zannoni G.F., Monterossi G., De Stefano I., Gargini A., Salerno M.G., Farulla I., Travaglia D., Vellone V.G., Scambia G. and Gallo D., The expression ratios of estrogen receptor alpha (ERalpha) to estrogen receptor beta1 (ERbeta1) and ERalpha to ERbeta2 identify poor clinical outcome in endometrioid endometrial cancer, Hum Pathol 44 (2013), 1047–1054. [DOI] [PubMed] [Google Scholar]

[ref009] [9]. Che Q., Liu B.Y., Wang F.Y., He Y.Y., Lu W., Liao Y., Gu W. and Wan X.P., Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK-NF-kappaB signaling pathway, Biochem Biophys Res Commun 446 (2014), 167–172. [DOI] [PubMed] [Google Scholar]

[ref010] [10]. Stoian S.C., Simionescu C., Margaritescu C., Stepan A. and Nurciu M., Endometrial carcinomas: correlation between ER, PR, Ki67 status and histopathological prognostic parameters, Rom J Morphol Embryol 52 (2011), 631–636. [PubMed] [Google Scholar]

[ref011] [11]. Porichi O., Nikolaidou M.E., Apostolaki A., Arnogiannaki N., Papassideri I., Chatonidis I., Tserkezoglou A., Vorgias G., Kassanos D. and Panotopoulou E., Isomorph expression of BAG-1 gene, ER and PR in endometrial cancer, Anticancer Res 30 (2010), 4103–4108. [PubMed] [Google Scholar]

[ref012] [12]. Srijaipracharoen S., Tangjitgamol S., Tanvanich S., Manusirivithaya S., Khunnarong J., Thavaramara T., Leelahakorn S. and Pataradool K., Expression of ER, PR, and Her-2/neu in endometrial cancer: a clinicopathological study, Asian Pac J Cancer Prev 11 (2010), 215–220. [PubMed] [Google Scholar]

[ref013] [13]. Wang Y., Zhu Y., Zhang L., Tian W., Hua S., Zhao J., Zhang H. and Xue F., Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway, Cancer Lett 322 (2012), 223–231. [DOI] [PubMed] [Google Scholar]

[ref014] [14]. Mizumoto Y., Kyo S., Mori N., Sakaguchi J., Ohno S., Maida Y., Hashimoto M., Takakura M. and Inoue M., Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis, Cancer Sci 98 (2007), 652–658. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref015] [15]. Shang C., Lu Y.M. and Meng L.R., KCC1 gene advances cell invasion ability by regulating ERK signaling pathway in endometrial cancer HEC-1B cell line, Int J Gynecol Cancer 21 (2011), 795–799. [DOI] [PubMed] [Google Scholar]

[ref016] [16]. Kousteni S., Bellido T., Plotkin L.I., O’Brien C.A., Bodenner D.L., Han L., Han K., DiGregorio G.B., Katzenellenbogen J.A., Katzenellenbogen B.S., Roberson P.K., Weinstein R.S., Jilka R.L. and Manolagas S.C., Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity, Cell 104 (2001), 719–730. [PubMed] [Google Scholar]

[ref017] [17]. Tong J.S., Zhang Q.H., Wang Z.B., Li S., Yang C.R., Fu X.Q., Hou Y., Wang Z.Y., Sheng J. and Sun Q.Y., ER-alpha36, a novel variant of ER-alpha, mediates estrogen-stimulated proliferation of endometrial carcinoma cells via the PKCdelta/ERK pathway, PLoS One 5 (2010), e15408. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref018] [18]. Nakopoulou L., Mylona E., Rafailidis P., Alexandrou P., Giannopoulou I. and Keramopoulos A., Effect of different ERK2 protein localizations on prognosis of patients with invasive breast carcinoma, APMIS 113 (2005), 693–701. [DOI] [PubMed] [Google Scholar]

[ref019] [19]. Lin S.L., Yan L.Y., Liang X.W., Wang Z.B., Wang Z.Y., Qiao J., Schatten H. and Sun Q.Y., A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hec1A cells, Reprod Biol Endocrinol 7 (2009), 102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[ref020] [20]. Treeck O., Diedrich K. and Ortmann O., The activation of an extracellular signal-regulated kinase by oestradiol interferes with the effects of trastuzumab on HER2 signalling in endometrial adenocarcinoma cell lines, Eur J Cancer 39 (2003), 1302–1309. [DOI] [PubMed] [Google Scholar]

PERMALINK

The expression of ER, PR in endometrial cancer and analysis of their correlation with ERK signaling pathway

Lan Luo

Lina Xu

Liang Tang

Abstract

1. Introduction