期刊论文详细信息
BMC Cancer
Differential expression patterns and clinical significance of estrogen receptor-α and β in papillary thyroid carcinoma
Yanhong Huang1  Wenwu Dong2  Jing Li1  Hao Zhang2  Zhongyan Shan1  Weiping Teng1 
[1] Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital, China Medical University, Liaoning Provincial Key Laboratory of Endocrine Diseases, Shenyang 110001, P. R. China
[2] Department of General Surgery, The First Affiliated Hospital, China Medical University, Shenyang 110001, P.R. China
关键词: VEGF;    Mutant P53;    Ki-67;    Papillary thyroid cancer;    ERβ1;    ERα;   
Others  :  1125403
DOI  :  10.1186/1471-2407-14-383
 received in 2014-04-29, accepted in 2014-05-26,  发布年份 2014
PDF
【 摘 要 】

Background

The incidence of papillary thyroid cancer (PTC) is markedly higher in women than men during the reproductive years. In vitro studies have suggested that estrogen may play an important role in the development and progression of PTC through estrogen receptors (ERs). This study aimed to investigate the expression patterns of the two main ER subtypes, α and β1 (wild-type ERβ), in PTC tissue and their clinical significance.

Methods

Immunohistochemical staining of thyroid tissue sections was performed to detect ER expression in female patients with PTC (n = 89) and nodular thyroid goiter (NTG; n = 30) using the Elivision™ plus two-step system. The relationships between ER subtype expression and clinicopathological/biological factors were further analyzed.

Results

The positive percentage and expression levels of ERα were significantly higher in female PTC patients of reproductive age (18–45 years old; n = 50) than age-matched female NTG patients (n = 30), while ERβ1 exhibited the opposite pattern. There was no difference in ERα or ERβ1 expression between female PTC patients of reproductive age and those of advanced reproductive age (>45 years old; n = 39). In the female PTC patients of reproductive age, ERα expression level was positively correlated with that of Ki-67, while ERβ1 was negatively correlated with mutant P53. Furthermore, more patients with exclusively nuclear ERα expression had extrathyroidal extension (ETE) as compared with those with extranuclear ERα localization. VEGF expression was significantly decreased in female PTC patients of reproductive age with only nuclear ERβ1 expression when compared with those with extranuclear ERβ1 localization. In PTC patients of advanced reproductive age, neither ERα nor ERβ1 expression showed any correlation with that of Ki-67, mutant P53, VEGF, tumor size, TNM stage, ETE, or lymph node metastases.

Conclusions

The differential expression patterns of the two ER subtypes between PTC and NTG indicate that ERα may be a useful immunohistochemical marker for differential diagnosis of PTC. The associations of ER subtype expression with Ki-67, mutant P53, VEGF expression and ETE in female PTC patients of reproductive age suggest that estrogen-activated ERα may mediate stimulatory effects on PTC growth and progression whereas ERβ1 has some inhibitory actions.

【 授权许可】

   
2014 Huang et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20150217020549534.pdf 686KB PDF download
Figure 2. 33KB Image download
Figure 1. 48KB Image download
【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】
  • [1]Rahbari R, Zhang L, Kebebew E: Thyroid cancer gender disparity. Future Oncol 2010, 6:1771-1779.
  • [2]Xing M: BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev 2007, 28:742-762.
  • [3]Kilfoy BA, Devesa SS, Ward MH, Zhang Y, Rosenberg PS, Holford TR, Anderson WF: Gender is an age-specific effect modifier for papillary cancers of the thyroid gland. Cancer Epidemiol Biomarkers Prev 2009, 18:1092-1100.
  • [4]Rajoria S, Suriano R, George AL, Shanmugam A, Jussim C, Shin EJ, Moscatello AL, Geliebter J, Carpi A, Tiwari RK: Estrogen activity as a preventive and therapeutic target in thyroid cancer. Biomed Pharmacother 2012, 66:151-158.
  • [5]Brindel P, Doyon F, Rachedi F, Boissin JL, Sebbag J, Shan L, Chungue V, Sun LY, Bost-Bezeaud F, Petitdidier P, Paoaafaite J, Teuri J, de Vathaire F: Menstrual and reproductive factors in the risk of differentiated thyroid carcinoma in native women in French Polynesia: a population-based case–control study. Am J Epidemiol 2008, 167:219-229.
  • [6]Renoir JM, Marsaud V, Lazennec G: Estrogen receptor signaling as a target for novel breast cancer therapeutics. Biochem Pharmacol 2013, 85:449-465.
  • [7]Koos RD: Minireview: Putting physiology back into estrogens’ mechanism of action. Endocrinology 2011, 152:4481-4488.
  • [8]Santin AP, Furlanetto TW: Role of estrogen in thyroid function and growth regulation. J Thyroid Res 2011, 2011:875125.
  • [9]Kamat A, Rajoria S, George A, Suriano R, Shanmugam A, Megwalu U, Prakash PB, Tiwari R, Schantz S: Estrogen-mediated angiogenesis in thyroid tumor microenvironment is mediated through VEGF signaling pathways. Arch Otolaryngol Head Neck Surg 2011, 137:1146-1153.
  • [10]Dong W, Zhang H, Li J, Guan H, He L, Wang Z, Shan Z, Teng W: Estrogen Induces Metastatic Potential of Papillary Thyroid Cancer Cells through Estrogen Receptor alpha and beta. Int J Endocrinol 2013, 2013:941568.
  • [11]di Vito M, de Santis E, Perrone GA, Mari E, Giordano MC, de Antoni E, Coppola L, Fadda G, Tafani M, Carpi A, Russo MA: Overexpression of estrogen receptor-alpha in human papillary thyroid carcinomas studied by laser- capture microdissection and molecular biology. Cancer Sci 2011, 102:1921-1927.
  • [12]Cheng S, Serra S, Mercado M, Ezzat S, Asa SL: A high-throughput proteomic approach provides distinct signatures for thyroid cancer behavior. Clin Cancer Res 2011, 17:2385-2394.
  • [13]Tavangar SM, Monajemzadeh M, Larijani B, Haghpanah V: Immunohistochemical study of oestrogen receptors in 351 human thyroid glands. Singapore Med J 2007, 48:744-747.
  • [14]Mete O, Rotstein L, Asa SL: Controversies in thyroid pathology: thyroid capsule invasion and extrathyroidal extension. Ann Surg Oncol 2010, 17:386-391.
  • [15]Kanehira K, Hu J, Pier T, Sebree L, Huang W: High endogenous avidin binding activity: an inexpensive and readily available marker for the differential diagnosis of kidney neoplasms. Int J Clin Exp Pathol 2008, 1:435-439.
  • [16]Lian Y, Li J, Huang Y, Dong W, Shan Z, Teng W, Zhang H: Endogenous avidin-binding activity in papillary thyroid carcinoma and nodular goiter tissues and its clinical significance. Endocrine 2012, 32:466-468.
  • [17]Allred DC, Harvey JM, Berardo M, Clark GM: Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998, 11:155-168.
  • [18]Ranjbari N, Rahim F: The Ki-67/MIB-1 index level and recurrence of papillary thyroid carcinoma. Med Hypotheses 2013, 80:311-314.
  • [19]Jansson A, Gentile M, Sun XF: p53 Mutations are present in colorectal cancer with cytoplasmic p53 accumulation. Int J Cancer 2001, 92:338-341.
  • [20]Stretch JR, Gatter KC, Ralfkiaer E, Lane DP, Harris AL: Expression of mutant p53 in melanoma. Cancer Res 1991, 51:5976-5979.
  • [21]Roger L, Gadea G, Roux P: Control of cell migration: a tumour suppressor function for p53? Biol Cell 2006, 98:141-152.
  • [22]Balta AZ, Filiz AI, Kurt Y, Sucullu I, Yucel E, Akin ML: Prognostic value of oncoprotein expressions in thyroid papillary carcinoma. Med Oncol 2012, 29:734-741.
  • [23]Bachmann K, Pawliska D, Kaifi J, Schurr P, Zorb J, Mann O, Kahl HJ, Izbicki JR, Strate T: P53 is an independent prognostic factor for survival in thyroid cancer. Anticancer Res 2007, 27:3993-3997.
  • [24]Salajegheh A, Pakneshan S, Rahman A, Dolan-Evans E, Zhang S, Kwong E, Gopalan V, Lo CY, Smith RA, Lam AK: Co-regulatory potential of vascular endothelial growth factor-A and vascular endothelial growth factor-C in thyroid carcinoma. Hum Pathol 2013, 44:2204-2212.
  • [25]Levin ER: Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol 2005, 19:1951-1959.
  • [26]Liu L, Chirala M, Younes M: Expression of estrogen receptor-beta isoforms in Barrett’s metaplasia, dysplasia and esophageal adenocarcinoma. Anticancer Res 2004, 24:2919-2924.
  • [27]Yan M, Rayoo M, Takano EA, Fox SB: Nuclear and cytoplasmic expressions of ERbeta1 and ERbeta2 are predictive of response to therapy and alters prognosis in familial breast cancers. Breast Cancer Res Treat 2011, 126:395-405.
  • [28]Shanle EK, Xu W: Selectively targeting estrogen receptors for cancer treatment. Adv Drug Deliv Rev 2010, 62:1265-1276.
  • [29]Bozkurt KK, Kapucuoglu N: Investigation of immunohistochemical ERalpha, ERbeta and ERbetacx expressions in normal and neoplastic breast tissues. Pathol Res Pract 2012, 208:133-139.
  • [30]Collins F, MacPherson S, Brown P, Bombail V, Williams AR, Anderson RA, Jabbour HN, Saunders PT: Expression of oestrogen receptors, ERalpha, ERbeta, and ERbeta variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERalpha. BMC Cancer 2009, 9:330. BioMed Central Full Text
  • [31]Heffner LJ: Advanced maternal age–how old is too old? N Engl J Med 2004, 351:1927-1929.
  • [32]Belchetz PE: Hormonal treatment of postmenopausal women. N Engl J Med 1994, 330:1062-1071.
  • [33]Edge SB, Compton CC: The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010, 17:1471-1474.
  • [34]Inoue H, Oshimo K, Miki H, Kawano M, Monden Y: Immunohistochemical study of estrogen receptors and the responsiveness to estrogen in papillary thyroid carcinoma. Cancer 1993, 72:1364-1368.
  • [35]Vannucchi G, Perrino M, Rossi S, Colombo C, Vicentini L, Dazzi D, Beck-Peccoz P, Fugazzola L: Clinical and molecular features of differentiated thyroid cancer diagnosed during pregnancy. Eur J Endocrinol 2010, 162:145-151.
  • [36]Zeng Q, Chen G, Vlantis A, Tse G, van Hasselt C: The contributions of oestrogen receptor isoforms to the development of papillary and anaplastic thyroid carcinomas. J Pathol 2008, 214:425-433.
  • [37]Heikkila A, Hagstrom J, Maenpaa H, Louhimo J, Siironen P, Heiskanen I, Haglund C, Arola J: Loss of estrogen receptor Beta expression in follicular thyroid carcinoma predicts poor outcome. Thyroid 2013, 23:456-465.
  • [38]Magri F, Capelli V, Rotondi M, Leporati P, La Manna L, Ruggiero R, Malovini A, Bellazzi R, Villani L, Chiovato L: Expression of estrogen and androgen receptors in differentiated thyroid cancer: an additional criterion to assess the patient’s risk. Endocr Relat Cancer 2012, 19:463-471.
  • [39]Dong W, Li J, Huang Y, Zhang H, Shan Z, Teng W: Differential expression patterns of estrogen receptor (ER)-beta splice variants between papillary thyroid cancer and nodular thyroid goiter. Med Sci Monit 2012, 18:BR351-BR355.
  • [40]Tan A, Etit D, Bayol U, Altinel D, Tan S: Comparison of proliferating cell nuclear antigen, thyroid transcription factor-1, Ki-67, p63, p53 and high-molecular weight cytokeratin expressions in papillary thyroid carcinoma, follicular carcinoma, and follicular adenoma. Ann Diagn Pathol 2011, 15:108-116.
  • [41]Tallini G, Garcia-Rostan G, Herrero A, Zelterman D, Viale G, Bosari S, Carcangiu ML: Downregulation of p27KIP1 and Ki67/Mib1 labeling index support the classification of thyroid carcinoma into prognostically relevant categories. Am J Surg Pathol 1999, 23:678-685.
  • [42]Asioli S, Erickson LA, Sebo TJ, Zhang J, Jin L, Thompson GB, Lloyd RV: Papillary thyroid carcinoma with prominent hobnail features: a new aggressive variant of moderately differentiated papillary carcinoma. A clinicopathologic, immunohistochemical, and molecular study of eight cases. Am J Surg Pathol 2010, 34:44-52.
  • [43]Ito Y, Miyauchi A: Prognostic factors of papillary and follicular carcinomas in Japan based on data of kuma hospital. J Thyroid Res 2012, 2012:973497.
  • [44]Sheri A, Dowsett M: Developments in Ki67 and other biomarkers for treatment decision making in breast cancer. Ann Oncol 2012, 23(Suppl 10):x219-x227.
  • [45]Mussig K, Wehrmann T, Dittmann H, Wehrmann M, Ueberberg B, Schulz S, Bares R, Petersenn S: Expression of the proliferation marker Ki-67 associates with tumour staging and clinical outcome in differentiated thyroid carcinomas. Clin Endocrinol (Oxf) 2012, 77:139-145.
  • [46]Zeng Q, Chen GG, Vlantis AC, van Hasselt CA: Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor-ERK pathway. Cell Prolif 2007, 40:921-935.
  • [47]Chen GG, Vlantis AC, Zeng Q, van Hasselt CA: Regulation of cell growth by estrogen signaling and potential targets in thyroid cancer. Curr Cancer Drug Targets 2008, 8:367-377.
  • [48]Goldstein I, Marcel V, Olivier M, Oren M, Rotter V, Hainaut P: Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies. Cancer Gene Ther 2011, 18:2-11.
  • [49]Koo JS, Shin E, Hong SW: Immunohistochemical characteristics of diffuse sclerosing variant of papillary carcinoma: comparison with conventional papillary carcinoma. APMIS 2010, 118:744-752.
  • [50]Morita N, Ikeda Y, Takami H: Clinical significance of p53 protein expression in papillary thyroid carcinoma. World J Surg 2008, 32:2617-2622.
  • [51]Gauchotte G, Philippe C, Lacomme S, Leotard B, Wissler MP, Allou L, Toussaint B, Klein M, Vignaud JM, Bressenot A: BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: evidence for multistep carcinogenesis. Pathology 2011, 43:447-452.
  • [52]Farid NR: P53 mutations in thyroid carcinoma: tidings from an old foe. J Endocrinol Invest 2001, 24:536-545.
  • [53]O’Brate A, Giannakakou P: The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist Updat 2003, 6:313-322.
  • [54]Ardito G, Revelli L, Boninsegna A, Sgambato A, Moschella F, Marzola MC, Giustozzi E, Avenia N, Castelli M, Rubello D: Immunohistochemical evaluation of inflammatory and proliferative markers in adjacent normal thyroid tissue in patients undergoing total thyroidectomy: results of a preliminary study. J Exp Clin Cancer Res 2010, 29:77. BioMed Central Full Text
  • [55]Menendez D, Inga A, Resnick MA: Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences. Proc Natl Acad Sci U S A 2010, 107:1500-1505.
  • [56]Erdem H, Gundogdu C, Sipal S: Correlation of E-cadherin, VEGF, COX-2 expression to prognostic parameters in papillary thyroid carcinoma. Exp Mol Pathol 2011, 90:312-317.
  • [57]Tian X, Cong M, Zhou W, Zhu J, Liu Q: Relationship between protein expression of VEGF-C, MMP-2 and lymph node metastasis in papillary thyroid cancer. J Int Med Res 2008, 36:699-703.
  • [58]Shin JA, Yang SJ, Jeong SI, Park HJ, Choi YH, Park EM: Activation of estrogen receptor beta reduces blood–brain barrier breakdown following ischemic injury. Neuroscience 2013, 235:165-173.
  • [59]Lim W, Park Y, Cho J, Park C, Park J, Park YK, Park H, Lee Y: Estrogen receptor beta inhibits transcriptional activity of hypoxia inducible factor-1 through the downregulation of arylhydrocarbon receptor nuclear translocator. Breast Cancer Res 2011, 13:R32. BioMed Central Full Text
  • [60]Thomas C, Rajapaksa G, Nikolos F, Hao R, Katchy A, McCollum CW, Bondesson M, Quinlan P, Thompson A, Krishnamurthy S, Esteva FJ, Gustafsson JA: ERbeta1 represses basal breast cancer epithelial to mesenchymal transition by destabilizing EGFR. Breast Cancer Res 2012, 14:R148. BioMed Central Full Text
  文献评价指标  
  下载次数:12次 浏览次数:11次