Expression of Estrogen-induced Genes and Estrogen Receptor β in Pancreatic Neuroendocrine Tumors: Implications for Targeted Therapy

Overview

Journal Pancreas

Specialty Gastroenterology

Date 2014 Jul 25

PMID 25058880

Citations 16

Authors

Jeannelyn S Estrella

Ly T Ma

Denai R Milton

James C Yao

Huamin Wang

Asif Rashid

Russell R Broaddus

Affiliations

Soon will be listed here.

Abstract

Objective: The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors.

Methods: Immunohistochemical expression of estrogen receptors (ERs) α and β as well as messenger RNA expression of estrogen-induced genes (PR, EIG121, IGF-1, IGF-1R, sFRP1, and sFRP4) by quantitative reverse transcription-polymerase chain reaction were examined in 131 World Health Organization grade G1 and G2 PanNETs and correlated their expression with clinicopathological features.

Results: Thirty-nine PanNETs (30%) showed high positive ERβ staining, and 87 cases (66%) had low positive ERβ staining; only 5 cases (4%) had no nuclear staining. Pancreatic neuroendocrine tumors with small size (P = 0.02), low World Health Organization grade (P = 0.02), and low American Joint Committee on Cancer stage (P = 0.006) more frequently showed high positive ERβ staining. Among the estrogen-induced genes studied, PanNETs had significantly higher expression of PR, EIG121, IGF-1, sFRP1, and sFRP4 compared with normal pancreas, independent of age or sex. High positive ERβ staining was associated with an increased expression of PR (P < 0.001) and EIG121 (P = 0.02).

Conclusions: Our study showed that PanNETs with favorable prognostic features have higher ERβ expression, which is associated with up-regulated PR and EIG121 messenger RNA expression. Estrogen regulation in PanNETs could potentially help in risk stratification and provide a rational target for novel treatment strategies.

Citing Articles

Neuroendocrine tumours and pregnancy: Real-world data from an European Neuroendocrine Tumour Centre of Excellence.

Ratnayake G, Shekhda K, Glover T, Al-Obudi Y, Hayes A, Armonis P J Neuroendocrinol. 2024; 37(1):e13465.

PMID: 39503166 PMC: 11750320. DOI: 10.1111/jne.13465.

[Gender medicine: endocrine and neuroendocrine diseases : Implications for surgery and perioperative management].

Butz F, Muller-Debus C, Mogl M Chirurgie (Heidelb). 2024; 95(9):736-741.

PMID: 39102037 DOI: 10.1007/s00104-024-02140-8.

Association Between Female Sex and Better Survival in Gastroenteropancreatic Neuroendocrine Tumors.

Chang J, Suraju M, Tran C, Chan C, Ear P, Howe J J Surg Res. 2024; 302:53-63.

PMID: 39083906 PMC: 11490409. DOI: 10.1016/j.jss.2024.07.012.

Sex Differences in the Survival of Patients with Neuroendocrine Neoplasms: A Comparative Study of Two National Databases.

Mortagy M, Asmar M, Chandrakumaran K, Ramage J Cancers (Basel). 2024; 16(13).

PMID: 39001438 PMC: 11240657. DOI: 10.3390/cancers16132376.

Epidemiological characteristics of neuroendocrine neoplasms in Beijing: a population-based retrospective study.

Chi Y, Liu S, Zhang J, Li H, Yang L, Zhang X BMC Public Health. 2024; 24(1):1396.

PMID: 38789981 PMC: 11127419. DOI: 10.1186/s12889-024-18845-8.

References

Picard F, Wanatabe M, Schoonjans K, Lydon J, OMalley B, Auwerx J . Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation. Proc Natl Acad Sci U S A. 2002; 99(24):15644-8. PMC: 137770. DOI: 10.1073/pnas.202612199. View

Onate S, Boonyaratanakornkit V, Spencer T, Tsai S, Tsai M, Edwards D . The steroid receptor coactivator-1 contains multiple receptor interacting and activation domains that cooperatively enhance the activation function 1 (AF1) and AF2 domains of steroid receptors. J Biol Chem. 1998; 273(20):12101-8. DOI: 10.1074/jbc.273.20.12101. View

Alabraba E, Taniere P, Reynolds G, Stewart P, Wigmore S, Bramhall S . Expression and functional consequences of oestrogen and progesterone receptors in human insulinomas. Endocr Relat Cancer. 2007; 14(4):1081-8. DOI: 10.1677/ERC-07-0093. View

Bilimoria K, Bentrem D, Merkow R, Tomlinson J, Stewart A, Ko C . Application of the pancreatic adenocarcinoma staging system to pancreatic neuroendocrine tumors. J Am Coll Surg. 2007; 205(4):558-63. DOI: 10.1016/j.jamcollsurg.2007.05.009. View

Paruthiyil S, Parmar H, Kerekatte V, Cunha G, Firestone G, Leitman D . Estrogen receptor beta inhibits human breast cancer cell proliferation and tumor formation by causing a G2 cell cycle arrest. Cancer Res. 2004; 64(1):423-8. DOI: 10.1158/0008-5472.can-03-2446. View

Viale G, Doglioni C, Gambacorta M, Zamboni G, Coggi G, Bordi C . Progesterone receptor immunoreactivity in pancreatic endocrine tumors. An immunocytochemical study of 156 neuroendocrine tumors of the pancreas, gastrointestinal and respiratory tracts, and skin. Cancer. 1992; 70(9):2268-77. DOI: 10.1002/1097-0142(19921101)70:9<2268::aid-cncr2820700910>3.0.co;2-x. View

Smith J, Reidy-Lagunes D . The management of extrapulmonary poorly differentiated (high-grade) neuroendocrine carcinomas. Semin Oncol. 2013; 40(1):100-8. DOI: 10.1053/j.seminoncol.2012.11.011. View

Magnaterra R, Porzio O, Piemonte F, Bertoli A, Sesti G, Lauro D . The effects of pregnancy steroids on adaptation of beta cells to pregnancy involve the pancreatic glucose sensor glucokinase. J Endocrinol. 1998; 155(2):247-53. DOI: 10.1677/joe.0.1550247. View

Tetu B, Ro J, Ayala A, Johnson D, Logothetis C, Ordonez N . Small cell carcinoma of the prostate. Part I. A clinicopathologic study of 20 cases. Cancer. 1987; 59(10):1803-9. DOI: 10.1002/1097-0142(19870515)59:10<1803::aid-cncr2820591019>3.0.co;2-x. View

10.

Tremblay G, Tremblay A, Copeland N, Gilbert D, Jenkins N, Labrie F . Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol. 1997; 11(3):353-65. DOI: 10.1210/mend.11.3.9902. View

11.

Nieuwenhuizen A, Schuiling G, Hilbrands L, Bisschop E, Koiter T . Proliferation of pancreatic islet-cells in cyclic and pregnant rats after treatment with progesterone. Horm Metab Res. 1999; 30(11):649-55. DOI: 10.1055/s-2007-978952. View

12.

Allred D, Carlson R, Berry D, Burstein H, Edge S, Goldstein L . NCCN Task Force Report: Estrogen Receptor and Progesterone Receptor Testing in Breast Cancer by Immunohistochemistry. J Natl Compr Canc Netw. 2009; 7 Suppl 6:S1-S21. DOI: 10.6004/jnccn.2009.0079. View

13.

Gallo D, De Stefano I, Prisco M, Scambia G, Ferrandina G . Estrogen receptor beta in cancer: an attractive target for therapy. Curr Pharm Des. 2012; 18(19):2734-57. DOI: 10.2174/138161212800626139. View

14.

Alonso-Magdalena P, Ropero A, Garcia-Arevalo M, Soriano S, Quesada I, Muhammed S . Antidiabetic actions of an estrogen receptor β selective agonist. Diabetes. 2013; 62(6):2015-25. PMC: 3661616. DOI: 10.2337/db12-1562. View

15.

Jarvinen T, Pelto-Huikko M, Holli K, Isola J . Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol. 2000; 156(1):29-35. PMC: 1868617. DOI: 10.1016/s0002-9440(10)64702-5. View

16.

Gosden J, Middleton P, Rout D . Localization of the human oestrogen receptor gene to chromosome 6q24----q27 by in situ hybridization. Cytogenet Cell Genet. 1986; 43(3-4):218-20. DOI: 10.1159/000132325. View

17.

Fuqua S, Schiff R, Parra I, Moore J, Mohsin S, Osborne C . Estrogen receptor beta protein in human breast cancer: correlation with clinical tumor parameters. Cancer Res. 2003; 63(10):2434-9. PMC: 4482102. View

18.

Deng L, Broaddus R, McCampbell A, Shipley G, Loose D, Stancel G . Identification of a novel estrogen-regulated gene, EIG121, induced by hormone replacement therapy and differentially expressed in type I and type II endometrial cancer. Clin Cancer Res. 2005; 11(23):8258-64. DOI: 10.1158/1078-0432.CCR-05-1189. View

19.

Harvey J, Clark G, Osborne C, Allred D . Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999; 17(5):1474-81. DOI: 10.1200/JCO.1999.17.5.1474. View

20.

Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P . Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index,.... Hum Pathol. 1996; 27(11):1124-34. DOI: 10.1016/s0046-8177(96)90303-2. View