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 1/2015

Open Access 01-12-2015 | Research article

Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas

Authors: Hua Gao, Fei Wang, Xiaolei Lan, Chuzhong Li, Jie Feng, Jiwei Bai, Lei Cao, Songbai Gui, Lichuan Hong, Yazhuo Zhang

Published in: BMC Cancer | Issue 1/2015

Login to get access

Abstract

Background

Dopamine agonists (DAs) are the first-line treatment for prolactinomas, which account for 25–30% of functioning pituitary adenomas, and bromocriptine (BRC) is the only commercially available DAs in China. However, tumors are resistant to therapy in 5–18% of patients.

Methods

The exomes of six responsive prolactinomas and six resistant prolactinomas were analyzed by whole-exome sequencing.

Results

Using stringent variant calling and filtering parameters, ten somatic variants that were mainly associated with DNA repair or protein metabolic processes were identified. New resistant variants were identified in multiple genes including PRDM2, PRG4, MUC4, DSPP, DPCR1, RP1L1, MX2, POTEF, C1orf170, and KRTAP10-3. The expression of these genes was then quantified by real-time reverse-transcription PCR (RT–qPCR) in 12 prolactinomas and 3 normal pituitary glands. The mRNA levels of PRDM2 were approximately five-fold lower in resistant prolactinomas than in responsive tumors (p < 0.05). PRDM2 protein levels were lower in resistant prolactinomas than in responsive tumors, as determined by Western blotting and immunohistochemical analysis (p < 0.05). Overexpression of PRDM2 upregulated dopamine receptor D2 (D2DR) and inhibited the phosphorylation of ERK1/2 in MMQ cells. PRDM2 showed a synergistic effect with BRC on the inhibition of prolactin (PRL) secretion and MMQ cell viability, and low PRDM2 expression was associated with tumor recurrence.

Conclusions

PRDM2 downregulation may play a role in dopamine-agonist resistance and tumor recurrence in prolactinomas.
Appendix
Available only for authorised users
Literature
1.
Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev. 2006;27(5):485–534.CrossRefPubMed
2.
Iyer P, Molitch ME. Positive prolactin response to bromocriptine in 2 patients with cabergoline-resistant prolactinomas. Endocr Pract. 2011;17(3):e55–8.CrossRefPubMed
3.
Wang F, Gao H, Li C, Bai J, Lu R, Cao L, et al. Low levels of PRB3 mRNA are associated with dopamine-agonist resistance and tumor recurrence in prolactinomas. J Neurooncol. 2014;116(1):83–8.CrossRefPubMed
4.
5.
Vroonen L, Daly A, Beckers A. Management of prolactinoma. Rev Med Suisse. 2013;9(395):1522–6.PubMed
6.
7.
8.
Osamura RY, Egashira N, Miyai S, Yamazaki M, Takekoshi S, Sanno N, et al. Molecular pathology of the pituitary. Development and functional differentiation of pituitary adenomas. Front Horm Res. 2004;32:20–33.CrossRefPubMed
9.
Gao H, Yang W, Qi Z, Lu L, Duan C, Zhao C, et al. DJ-1 protects dopaminergic neurons against rotenone-induced apoptosis by enhancing ERK-dependent mitophagy. J Mol Biol. 2012;423(2):232–48.CrossRefPubMed
10.
Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44(6):685–9.CrossRefPubMedPubMedCentral
11.
12.
13.
Raverot G, Wierinckx A, Dantony E, Auger C, Chapas G, Villeneuve L, et al. HYPOPRONOS. Prognostic factors in prolactin pituitary tumors: clinical, histological, and molecular data from a series of 94 patients with a long postoperative follow-up. J Clin Endocrinol Metab. 2010;95(4):1708–16.CrossRefPubMed
14.
Congdon LM, Sims JK, Tuzon CT, Rice JC. The PR-Set7 binding domain of Riz1 is required for the H4K20me1-H3K9me1 trans-tail ‘histone code’ and Riz1 tumor suppressor function. Nucleic Acids Res. 2014;42(6):3580–9.CrossRefPubMedPubMedCentral
15.
Pellegrini PI, Rasolonjanahary R, Gunz G, Bertrand P, Delivet S, Jedynak CP, et al. Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab. 1989;69(3):500–9.CrossRefPubMed
16.
Kukstas LA, Domec C, Bascles L, Bonnet J, Verrier D, Israel JM, et al. Different expression of the two dopaminergic D2 receptors, D2415 and D2444, in two types of lactotroph each characterised by their response to dopamine, and modification of expression by sex steroids. Endocrinology. 1991;129(2):1101–3.CrossRefPubMed
17.
Caccavelli L, Feron F, Morange I, Rouer E, Benarous R, Dewailly D, et al. Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology. 1994;60(3):314–22.CrossRefPubMed
18.
Wu ZB, Zheng WM, Su ZP, Chen Y, Wu JS, Wang CD, et al. Expression of D2RmRNA isoforms and ERmRNA isoforms in prolactinomas: correlation with the response to bromocriptine and with tumor biological behavior. J Neurooncol. 2010;99(1):25–32.CrossRefPubMed
19.
Pellegrini-Bouiller I, Morange-Ramos I, Barlier A, Gunz G, Figarella-Branger D, Cortet-Rudelli C, et al. Pit-1 gene expression in human lactotroph and somatotroph pituitary adenomas is correlated to D2 receptor gene expression. J Clin Endocrinol Metab. 1996;81(9):3390–6.PubMed
20.
Delgrange E, Sassolas G, Perrin G, Jan M, Trouillas J. Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance. Acta Neurochir (Wien). 2005;147(7):751–8.CrossRef
21.
Newey PJ, Nesbit MA, Rimmer AJ, Head RA, Gorvin CM, Attar M, et al. Whole-exome sequencing studies of nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 2013;98(4):E796–800.CrossRefPubMedPubMedCentral
22.
Buyse IM, Shao G, Huang S. The retinoblastoma protein binds to RIZ, a zinc-finger protein that shares an epitope with the adenovirus E1A protein. Proc Natl Acad Sci U S A. 1995;92(10):4467–71.CrossRefPubMedPubMedCentral
23.
Ng WT, Choi CW, Chan SH, Yau TK, Lee AW. Familial nasopharyngeal carcinoma in Hong Kong: epidemiology and implication in screening. Fam Cancer. 2009;8(2):103–8.CrossRefPubMed
24.
Liu ZY, Wang JY, Liu HH, Ma XM, Wang CL, Zhang XP, et al. Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) dysregulation in human malignant meningiomas. Oncogene. 2013;32(10):1216–22.CrossRefPubMed
25.
Szende B, Tyihak E. Effect of formaldehyde on cell proliferation and death. Cell Biol Int. 2010;34(12):1273–82.CrossRefPubMed
26.
Overmeer RM, Louwers JA, Meijer CJ, van Kemenade FJ, Hesselink AT, Daalmeijer NF, et al. Combined CADM1 and MAL promoter methylation analysis to detect (pre-)malignant cervical lesions in high-risk HPV-positive women. Int J Cancer. 2011;129(9):2218–25.CrossRefPubMed
27.
Dong SW, Zhang P, Liu YM, Cui YT, Wang S, Liang SJ, et al. Study on RIZ1 gene promoter methylation status in human esophageal squamous cell carcinoma. World J Gastroenterol. 2012;18(6):576–82.CrossRefPubMedPubMedCentral
28.
Dong SW, Li D, Xu C, Sun P, Wang YG, Zhang P. Alteration in gene expression profile and oncogenicity of esophageal squamous cell carcinoma by RIZ1 upregulation. World J Gastroenterol. 2013;19(37):6170–7.CrossRefPubMedPubMedCentral
29.
Sun W, Geyer CR, Yang J. Cloning, expression, purification and crystallization of the PR domain of human retinoblastoma protein-binding zinc finger protein 1 (RIZ1). Int J Mol Sci. 2008;9(6):943–50.CrossRefPubMedPubMedCentral
30.
Zhao F, Chen Y, Zeng LL, Li R, Zeng R, Wen L, et al. Effects of triptolide on RIZ1 expression, proliferation, and apoptosis in multiple myeloma U266 cells. Acta Pharmacol Sin. 2010;31(6):733–40.CrossRefPubMedPubMedCentral
31.
Chadwick RB, Jiang GL, Bennington GA, Yuan B, Johnson CK, Stevens MW, et al. Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis. Proc Natl Acad Sci U S A. 2000;97(6):2662–7.CrossRefPubMedPubMedCentral
32.
Xu RR, Xuan LN, Wang Y. Methylation status of RIZ1 gene promoter in myelodysplastic syndrome. Zhonghua Xue Ye Xue Za Zhi. 2012;33(9):774–5.PubMed
33.
Prysor-Jones RA, Jenkins JS. Effect of bromocriptine on DNA synthesis, growth and hormone secretion of spontaneous pituitary tumours in the rat.”. J Endocrinol. 1981;88(3):463–9.CrossRefPubMed
34.
LaPensee EW, Schwemberger SJ, LaPensee CR, el Bahassi M, Afton SE, Ben-Jonathan N. Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase. Carcinogenesis. 2009;30(8):1298–304.CrossRefPubMedPubMedCentral
35.
Murakami M, Mizutani A, Asano S, Katakami H, Ozawa Y, Yamazaki K, et al. A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma: case report. Neurosurgery. 2011;68(6):E1761–7.CrossRefPubMed
36.
Metadata
Title
Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas
Authors
Hua Gao
Fei Wang
Xiaolei Lan
Chuzhong Li
Jie Feng
Jiwei Bai
Lei Cao
Songbai Gui
Lichuan Hong
Yazhuo Zhang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1267-0

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Debate

Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential

Research article

APC selectively mediates response to chemotherapeutic agents in breast cancer

Research article

Dual role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor prognosis in early cancer and CD44ν is an indicator for recurrence in advanced cancer

Study protocol

The Breast Cancer to Bone (B2B) Metastases Research Program: a multi-disciplinary investigation of bone metastases from breast cancer

Research article

Number of negative lymph nodes is associated with disease-free survival in patients with breast cancer

Research article

A patient perspective on shared decision making in stage I non-small cell lung cancer: a mixed methods 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