Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis

Authors: Karen K. L. Chan, Michelle K. Y. Siu, Yu-xin Jiang, Jing-jing Wang, Yan Wang, Thomas H. Y. Leung, Stephanie S. Liu, Annie N. Y. Cheung, Hextan Y. S. Ngan

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Due to the presence of both classical estrogen receptor (ERα) and another ER subtype (ERβ) in ovarian cancer, hormonal treatment is an attractive option. However, response to tamoxifen in ovarian cancer is modest. The presence of ERβ variants further complicated the issue. We have recently shown that specifically targeting ER subtypes using selective ER modulators showed opposing functions of ER subtypes on cell growth. In the present study, the clinical significance of ERα and ERβ variants (β1, β2 and β5) and the functional effects of ERβ2 and ERβ5 in ovarian cancer was investigated.

Methods

ERα, ERβ1, ERβ2 and ERβ5 expression were evaluated by immunohistochemistry in 106 ovarian cancer tissues. The association between ERs expression and clinicopathological parameters or prognosis was analyzed. Ectopic expression of ERβ2 and ERβ5 followed by functional assays were performed in ovarian cancer cell lines in order to detect their effects on cell invasion and proliferation.

Results

We found significantly higher nuclear (n)ERα and nERβ5 and lower cytoplasmic (c)ERα expression in advanced cancers. Significantly lower ERβ1 expression was also detected in high grade cancers. Significant loss of nERα and cERβ2 expression were observed in clear cell histological subtypes. Higher nERβ5 and lower cERβ5 expression were associated with serous/clear cell subtypes, poor disease-free and overall survival. Positive cERα and higher cERβ1 expression were significantly associated with better disease-free and overall survival. Furthermore, we found nERβ5 as an independent prognostic factor for overall survival. Functionally, overexpression of ERβ5 enhanced ovarian cancer cell migration, invasion and proliferation via FAK/c-Src activation whereas ERβ2 induced cell migration and invasion.

Conclusions

Since tamoxifen binds to both ERα and ERβ1 which appear to bear opposing oncogenic roles, the histotypes-specific expression pattern of ERs indicates that personalized treatment for women based on ERs expression using selective estrogen receptor modulators may improve response rate. This study also suggests nERβ5 as a potential prognostic marker and therapeutic target in ovarian cancer.
Appendix
Available only for authorised users
Literature
1.
Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212–36.CrossRefPubMed
2.
Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3(7):502–16.CrossRefPubMed
3.
Modugno F, Laskey R, Smith AL, Andersen CL, Haluska P, Oesterreich S. Hormone response in ovarian cancer: time to reconsider as a clinical target? Endocr Relat Cancer. 2012;19(6):R255–79.CrossRefPubMedPubMedCentral
4.
Perez-Gracia JL, Carrasco EM. Tamoxifen therapy for ovarian cancer in the adjuvant and advanced settings: systematic review of the literature and implications for future research. Gynecol Oncol. 2002;84(2):201–9.CrossRefPubMed
5.
Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A. 1996;93(12):5925–30.CrossRefPubMedPubMedCentral
6.
Mosselman S, Polman J, Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett. 1996;392(1):49–53.CrossRefPubMed
7.
Lo R, Matthews J. A new class of estrogen receptor beta-selective activators. Mol Interv. 2010;10(3):133–6.CrossRefPubMed
8.
Chan KK, Wei N, Liu SS, Xiao-Yun L, Cheung AN, Ngan HY. Estrogen receptor subtypes in ovarian cancer: a clinical correlation. Obstet Gynecol. 2008;111(1):144–51.CrossRefPubMed
9.
Suzuki F, Akahira J, Miura I, Suzuki T, Ito K, Hayashi S, Sasano H, Yaegashi N. Loss of estrogen receptor beta isoform expression and its correlation with aberrant DNA methylation of the 5′-untranslated region in human epithelial ovarian carcinoma. Cancer Sci. 2008;99(12):2365–72.CrossRefPubMed
10.
Chan KK, Leung TH, Chan DW, Wei N, Lau GT, Liu SS, Siu MK, Ngan HY. Targeting estrogen receptor subtypes (ERalpha and ERbeta) with selective ER modulators in ovarian cancer. J Endocrinol. 2014;221(2):325–36.CrossRefPubMed
11.
Leung YK, Mak P, Hassan S, Ho SM. Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc Natl Acad Sci U S A. 2006;103(35):13162–7.CrossRefPubMedPubMedCentral
12.
Moore JT, McKee DD, Slentz-Kesler K, Moore LB, Jones SA, Horne EL, Su JL, Kliewer SA, Lehmann JM, Willson TM. Cloning and characterization of human estrogen receptor beta isoforms. Biochem Biophys Res Commun. 1998;247(1):75–8.CrossRefPubMed
13.
Wong NA, Malcomson RD, Jodrell DI, Groome NP, Harrison DJ, Saunders PT. ERbeta isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates. J Pathol. 2005;207(1):53–60.CrossRefPubMed
14.
Shaaban AM, Green AR, Karthik S, Alizadeh Y, Hughes TA, Harkins L, Ellis IO, Robertson JF, Paish EC, Saunders PT, et al. Nuclear and cytoplasmic expression of ERbeta1, ERbeta2, and ERbeta5 identifies distinct prognostic outcome for breast cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008;14(16):5228–35.CrossRef
15.
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.CrossRefPubMedPubMedCentral
16.
Leung YK, Lam HM, Wu S, Song D, Levin L, Cheng L, Wu CL, Ho SM. Estrogen receptor beta2 and beta5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion. Endocr Relat Cancer. 2010;17(3):675–89.CrossRefPubMedPubMedCentral
17.
Fujimura T, Takahashi S, Urano T, Ogawa S, Ouchi Y, Kitamura T, Muramatsu M, Inoue S. Differential expression of estrogen receptor beta (ERbeta) and its C-terminal truncated splice variant ERbetacx as prognostic predictors in human prostatic cancer. Biochem Biophys Res Commun. 2001;289(3):692–9.CrossRefPubMed
18.
Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 2007;87(3):905–31.CrossRefPubMed
19.
Zhang G, Liu X, Farkas AM, Parwani AV, Lathrop KL, Lenzner D, Land SR, Srinivas H. Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells. Mol Endocrinol. 2009;23(2):146–56.CrossRefPubMed
20.
Bardin A, Boulle N, Lazennec G, Vignon F, Pujol P. Loss of ERbeta expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer. 2004;11(3):537–51.CrossRefPubMedPubMedCentral
21.
Ciucci A, Zannoni GF, Travaglia D, Petrillo M, Scambia G, Gallo D. Prognostic significance of the estrogen receptor beta (ERbeta) isoforms ERbeta1, ERbeta2, and ERbeta5 in advanced serous ovarian cancer. Gynecol Oncol. 2014;132(2):351–9.CrossRefPubMed
22.
De Stefano I, Zannoni GF, Prisco MG, Fagotti A, Tortorella L, Vizzielli G, Mencaglia L, Scambia G, Gallo D. Cytoplasmic expression of estrogen receptor beta (ERbeta) predicts poor clinical outcome in advanced serous ovarian cancer. Gynecol Oncol. 2011;122(3):573–9.CrossRefPubMed
23.
Sieh W, Kobel M, Longacre TA, Bowtell DD, de Fazio A, Goodman MT, Hogdall E, Deen S, Wentzensen N, Moysich KB, et al. Hormone-receptor expression and ovarian cancer survival: an ovarian tumor tissue analysis consortium study. The lancet oncology. 2013;14(9):853–62.CrossRefPubMedPubMedCentral
24.
Siu MK, Chan HY, Kong DS, Wong ES, Wong OG, Ngan HY, Tam KF, Zhang H, Li Z, Chan QK, et al. p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients. Proc Natl Acad Sci U S A. 2010;107(43):18622–7.CrossRefPubMedPubMedCentral
25.
Siu MK, Wong ES, Kong DS, Chan HY, Jiang L, Wong OG, Lam EW, Chan KK, Ngan HY, Le XF, et al. Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and FoxJ1 and contributes to adverse clinical outcome in ovarian cancers. Oncogene. 2013;32(30):3500–9.CrossRefPubMed
26.
Zhao X, Guan JL. Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev. 2011;63(8):610–5.CrossRefPubMed
27.
Ward KK, Tancioni I, Lawson C, Miller NL, Jean C, Chen XL, Uryu S, Kim J, Tarin D, Stupack DG, et al. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clinical & experimental metastasis. 2013;30(5):579–94.CrossRef
28.
Spillman MA, Manning NG, Dye WW, Sartorius CA, Post MD, Harrell JC, Jacobsen BM, Horwitz KB. Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis. Cancer Res. 2010;70(21):8927–36.CrossRefPubMedPubMedCentral
29.
Welsh AW, Lannin DR, Young GS, Sherman ME, Figueroa JD, Henry NL, Ryden L, Kim C, Love RR, Schiff R, et al. Cytoplasmic estrogen receptor in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012;18(1):118–26.CrossRef
30.
Perez White B, Molloy ME, Zhao H, Zhang Y, Tonetti DA. Extranuclear ERalpha is associated with regression of T47D PKCalpha-overexpressing, tamoxifen-resistant breast cancer. Mol Cancer. 2013;12:34.CrossRefPubMedPubMedCentral
31.
Treeck O, Pfeiler G, Mitter D, Lattrich C, Piendl G, Ortmann O. Estrogen receptor {beta}1 exerts antitumoral effects on SK-OV-3 ovarian cancer cells. J Endocrinol. 2007;193(3):421–33.CrossRefPubMed
32.
Zhu J, Hua K, Sun H, Yu Y, Jin H, Feng Y. Re-expression of estrogen receptor beta inhibits the proliferation and migration of ovarian clear cell adenocarcinoma cells. Oncol Rep. 2011;26(6):1497–503.PubMed
33.
Bossard C, Busson M, Vindrieux D, Gaudin F, Machelon V, Brigitte M, Jacquard C, Pillon A, Balaguer P, Balabanian K, et al. Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer. PLoS One. 2012;7(9):e44787.CrossRefPubMedPubMedCentral
34.
Cheng J, Lee EJ, Madison LD, Lazennec G. Expression of estrogen receptor beta in prostate carcinoma cells inhibits invasion and proliferation and triggers apoptosis. FEBS Lett. 2004;566(1–3):169–72.CrossRefPubMed
35.
Green CA, Peter MB, Speirs V, Shaaban AM. The potential role of ER beta isoforms in the clinical management of breast cancer. Histopathology. 2008;53(4):374–80.CrossRefPubMed
36.
Liu Z, Liao Y, Tang H, Chen G. The expression of estrogen receptors beta2, 5 identifies and is associated with prognosis in non-small cell lung cancer. Endocrine. 2013;44(2):517–24.CrossRefPubMed
37.
Lee MT, Ho SM, Tarapore P, Chung I, Leung YK. Estrogen receptor beta isoform 5 confers sensitivity of breast cancer cell lines to chemotherapeutic agent-induced apoptosis through interaction with Bcl2L12. Neoplasia. 2013;15(11):1262–71.CrossRefPubMedPubMedCentral
38.
Ciucci A, Zannoni GF, Travaglia D, Scambia G, Gallo D. Mitochondrial estrogen receptor beta2 drives antiapoptotic pathways in advanced serous ovarian cancer. Hum Pathol. 2015;46(8):1138–46.CrossRefPubMed
39.
40.
Fujimura M, Hidaka T, Kataoka K, Yamakawa Y, Akada S, Teranishi A, Saito S. Absence of estrogen receptor-alpha expression in human ovarian clear cell adenocarcinoma compared with ovarian serous, endometrioid, and mucinous adenocarcinoma. Am J Surg Pathol. 2001;25(5):667–72.CrossRefPubMed
41.
Yamaguchi K, Huang Z, Matsumura N, Mandai M, Okamoto T, Baba T, Konishi I, Berchuck A, Murphy SK. Epigenetic determinants of ovarian clear cell carcinoma biology. International journal of cancer Journal international du cancer. 2014;135(3):585–97.CrossRefPubMedPubMedCentral
42.
Nilsson S, Koehler KF, Gustafsson JA. Development of subtype-selective oestrogen receptor-based therapeutics. Nat Rev Drug Discov. 2011;10(10):778–92.CrossRefPubMed
43.
Markman M, Iseminger KA, Hatch KD, Creasman WT, Barnes W, Dubeshter B. Tamoxifen in platinum-refractory ovarian cancer: a gynecologic oncology group ancillary report. Gynecol Oncol. 1996;62(1):4–6.CrossRefPubMed
44.
Trope C, Marth C, Kaern J. Tamoxifen in the treatment of recurrent ovarian carcinoma. Eur J Cancer. 2000;36(Suppl 4):S59–61.CrossRefPubMed
Metadata
Title
Differential expression of estrogen receptor subtypes and variants in ovarian cancer: effects on cell invasion, proliferation and prognosis
Authors
Karen K. L. Chan
Michelle K. Y. Siu
Yu-xin Jiang
Jing-jing Wang
Yan Wang
Thomas H. Y. Leung
Stephanie S. Liu
Annie N. Y. Cheung
Hextan Y. S. Ngan
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3601-1

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

microRNA-193a-3p is specifically down-regulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer

Research article

PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival

Research article

Trends in risk classification and primary therapy of Japanese patients with prostate cancer in Nara urological research and treatment group (NURTG) – comparison between 2004–2006, 2007–2009, and 2010–2012

Research article

Parity and bladder cancer risk: a dose-response meta-analysis

Research article

Identification of endonuclease domain-containing 1 as a novel tumor suppressor in prostate cancer

Research article

Central nervous system progression in advanced non–small cell lung cancer patients with EGFR mutations in response to first-line treatment with two EGFR-TKIs, gefitinib and erlotinib: a comparative study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits