J Pathol Transl Med.  2020 Jan;54(1):103-111. 10.4132/jptm.2019.10.12.

Expression of female sex hormone receptors and its relation to clinicopathological characteristics and prognosis of lung adenocarcinoma

• Lee JH
• Kim HK
• Shin BK

• KMID: 2501598
• DOI: http://doi.org/10.4132/jptm.2019.10.12

Abstract

Background
Adenocarcinoma (ADC) of the lung exhibits different clinicopathological characteristics in men and women. Recent studies have suggested that these differences originate from the expression of female sex hormone receptors in tumor cells. The aim of the present study was to evaluate the immunohistochemical expression of female sex hormone receptors in lung ADC and determine the expression patterns in patients with different clinicopathological characteristics.
Methods
A total of 84 patients with lung ADC who underwent surgical resection and/or core biopsy were recruited for the present study. Immunohistochemical staining was performed for estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR), epidermal growth factor receptor (EGFR), EGFR E746- A750 del, and EGFR L858R using tissue microarray.
Results
A total of 39 (46.4%) ERα-positive, 71 (84.5%) ERβ-positive, and 46 (54.8%) PR-positive lung ADCs were identified. In addition, there were 81 (96.4%) EGFR-positive, 14 (16.7%) EGFR E746-A750 del–positive, and 34 (40.5%) EGFR L858R–positive cases. The expression of female sex hormone receptors was not significantly different in clinicopathologically different subsets of lung ADC.
Conclusions
Expression of female sex hormone receptors is not associated with the prognosis and clinicopathological characteristics of patients with lung ADC.

Keyword

Adenocarcinoma of lung; Receptors, estrogen; ERα; ERβ; Receptors, progesterone; Prognosis

Figure

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  Fig. 1. Representative results of immunohistochemical staining. (A) Nuclear staining for estrogen receptor α. (B) Nuclear staining for estrogen receptor β. (C) Nuclear staining for progesterone receptor.

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  Fig. 2. Kaplan-Meier plots of progression-free survival (PFS) and overall survival (OS) in the age subgroups. (A) Estrogen receptor α (ERα) expression was associated with poor PFS in the age ≥ 65 years subgroup. (B) ERα expression was associated with poor OS in the age ≥ 65 years subgroup. (C) ERα expression was not associated with PFS in the age < 65 years subgroup. (D) ERα expression was not associated with OS in the age < 65 years subgroup.

Reference

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65:87–108.

2. Omoto Y, Kobayashi Y, Nishida K, et al. Expression, function, and clinical implications of the estrogen receptor beta in human lung cancers. Biochem Biophys Res Commun. 2001; 285:340–7.

3. Yano T, Miura N, Takenaka T, et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer. 2008; 113:1012–8.

4. Torday JS, Nielsen HC, Fencl Mde M, Avery ME. Sex differences in fetal lung maturation. Am Rev Respir Dis. 1981; 123:205–8.

5. Taioli E, Wynder EL. Re: Endocrine factors and adenocarcinoma of the lung in women. J Natl Cancer Inst. 1994; 86:869–70.

6. Henderson BE, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer. Cancer Res. 1982; 42:3232–9.

7. Mollerup S, Jørgensen K, Berge G, Haugen A. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer. 2002; 37:153–9.

8. Kawai H, Ishii A, Washiya K, et al. Combined overexpression of EGFR and estrogen receptor alpha correlates with a poor outcome in lung cancer. Anticancer Res. 2005; 25:4693–8.

9. Stabile LP, Dacic S, Land SR, et al. Combined analysis of estrogen receptor beta-1 and progesterone receptor expression identifies lung cancer patients with poor outcome. Clin Cancer Res. 2011; 17:154–64.

10. Hsu LH, Liu KJ, Tsai MF, et al. Estrogen adversely affects the prognosis of patients with lung adenocarcinoma. Cancer Sci. 2015; 106:51–9.

11. Schwartz AG, Prysak GM, Murphy V, et al. Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex. Clin Cancer Res. 2005; 11:7280–7.

12. Skov BG, Fischer BM, Pappot H. Oestrogen receptor beta over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer. 2008; 59:88–94.

13. Allred DC, Bustamante MA, Daniel CO, Gaskill HV, Cruz AB Jr. Immunocytochemical analysis of estrogen receptors in human breast carcinomas: evaluation of 130 cases and review of the literature regarding concordance with biochemical assay and clinical relevance. Arch Surg. 1990; 125:107–13.

14. Wen YH, Brogi E, Hasanovic A, et al. Immunohistochemical staining with EGFR mutation-specific antibodies: high specificity as a diagnostic marker for lung adenocarcinoma. Mod Pathol. 2013; 26:1197–203.

15. Patrone C, Cassel TN, Pettersson K, et al. Regulation of postnatal lung development and homeostasis by estrogen receptor beta. Mol Cell Biol. 2003; 23:8542–52.

16. Swedenborg E, Power KA, Cai W, Pongratz I, Rüegg J. Regulation of estrogen receptor beta activity and implications in health and disease. Cell Mol Life Sci. 2009; 66:3873–94.

17. Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995; 270:1491–4.

18. Nose N, Sugio K, Oyama T, et al. Association between estrogen receptor-beta expression and epidermal growth factor receptor mutation in the postoperative prognosis of adenocarcinoma of the lung. J Clin Oncol. 2009; 27:411–7.

19. Rouquette I, Lauwers-Cances V, Allera C, et al. Characteristics of lung cancer in women: importance of hormonal and growth factors. Lung Cancer. 2012; 76:280–5.

20. Kadota K, Eguchi T, Villena-Vargas J, et al. Nuclear estrogen receptor-alpha expression is an independent predictor of recurrence in male patients with pT1aN0 lung adenocarcinomas, and correlates with regulatory T-cell infiltration. Oncotarget. 2015; 6:27505–18.

21. Karlsson C, Helenius G, Fernandes O, Karlsson MG. Oestrogen receptor beta in NSCLC: prevalence, proliferative influence, prognostic impact and smoking. APMIS. 2012; 120:451–8.

22. Raso MG, Behrens C, Herynk MH, et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin Cancer Res. 2009; 15:5359–68.

23. Baik CS, Eaton KD. Estrogen signaling in lung cancer: an opportunity for novel therapy. Cancers (Basel). 2012; 4:969–88.

24. Gomez-Fernandez C, Mejias A, Walker G, Nadji M. Immunohistochemical expression of estrogen receptor in adenocarcinomas of the lung: the antibody factor. Appl Immunohistochem Mol Morphol. 2010; 18:137–41.

25. Di Nunno L, Larsson LG, Rinehart JJ, Beissner RS. Estrogen and progesterone receptors in non-small cell lung cancer in 248 consecutive patients who underwent surgical resection. Arch Pathol Lab Med. 2000; 124:1467–70.

26. Sun HB, Zheng Y, Ou W, et al. Association between hormone receptor expression and epidermal growth factor receptor mutation in patients operated on for non-small cell lung cancer. Ann Thorac Surg. 2011; 91:1562–7.

27. Mauro LV, Dalurzo M, Carlini MJ, et al. Estrogen receptor beta and epidermal growth factor receptor as early-stage prognostic biomarkers of non-small cell lung cancer. Oncol Rep. 2010; 24:1331–8.

28. Abe K, Miki Y, Ono K, et al. Highly concordant coexpression of aromatase and estrogen receptor beta in non-small cell lung cancer. Hum Pathol. 2010; 41:190–8.

29. Trotter A, Kipp M, Schrader RM, Beyer C. Combined application of 17beta-estradiol and progesterone enhance vascular endothelial growth factor and surfactant protein expression in cultured embryonic lung cells of mice. Int J Pediatr. 2009; 2009:170491.

30. Marquez-Garban DC, Mah V, Alavi M, et al. Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer. Steroids. 2011; 76:910–20.

31. Kishi S, Yokohira M, Yamakawa K, Saoo K, Imaida K. Significance of the progesterone receptor and epidermal growth factor receptor, but not the estrogen receptor, in chemically induced lung carcinogenesis in female A/J mice. Oncol Lett. 2014; 8:2379–86.

32. Toh CK, Ahmad B, Soong R, et al. Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas. J Thorac Oncol. 2010; 5:17–22.

33. Beattie CW, Hansen NW, Thomas PA. Steroid receptors in human lung cancer. Cancer Res. 1985; 45:4206–14.

34. Kaiser U, Hofmann J, Schilli M, et al. Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer. Int J Cancer. 1996; 67:357–64.

35. Berardi R, Morgese F, Santinelli A, et al. Hormonal receptors in lung adenocarcinoma: expression and difference in outcome by sex. Oncotarget. 2016; 7:82648–57.

36. Grant L, Banerji S, Murphy L, et al. Androgen receptor and Ki67 expression and survival outcomes in non-small cell lung cancer. Horm Cancer. 2018; 9:288–94.

37. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010; 29:37–48.

38. Hsu LH, Chu NM, Kao SH. Estrogen, estrogen receptor and lung cancer. Int J Mol Sci. 2017; 18:E713.

39. Zhao XZ, Liu Y, Zhou LJ, Wang ZQ, Wu ZH, Yang XY. Role of estrogen in lung cancer based on the estrogen receptor-epithelial mesenchymal transduction signaling pathways. Onco Targets Ther. 2015; 8:2849–63.

40. Fitzpatrick SL, Brightwell J, Wittliff JL, Barrows GH, Schultz GS. Epidermal growth factor binding by breast tumor biopsies and relationship to estrogen receptor and progestin receptor levels. Cancer Res. 1984; 44:3448–53.

41. Rimawi MF, Shetty PB, Weiss HL, et al. Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes. Cancer. 2010; 116:1234–42.

42. Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012; 136:331–45.