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01-07-2020 | Breast Cancer | Original Article

Increased Expression of Gankyrin and Stemness Factor Oct-4 are Associated with Unfavorable Clinical Outcomes and Poor Benefit of Tamoxifen in Breast Carcinoma Patients

Authors: Rosa Jahangiri, Fatemeh Mosaffa, Amirnader EmamiRazavi, Masoumeh Gharib, Khadijeh Jamialahmadi

Published in: Pathology & Oncology Research | Issue 3/2020

Abstract

Tamoxifen is the most important treatment component in estrogen receptor positive (ER+) breast carcinoma patients. Tamoxifen resistance incidence presents an important obstacle in clinical treatment. Mechanisms underlying tamoxifen refractory are not completely understood. Although elevated expression of Gankyrin (P28GANK) and stem cell markers Nanog, Oct-4 and Sox-2 have been reported in breast carcinoma, their role in tamoxifen resistance progression has not been explored. In the present study, P28GANK and stem cell markers Nanog, Oct-4 and Sox-2 expression were evaluated using quantitative RT-PCR and immunohistochemical technology in 72 breast carcinoma patients who received tamoxifen as adjuvant anti-hormone treatment. Expression data were correlated with the clinical outcome and survival of patients. Data analysis showed that P28GANK, Oct-4 and Sox-2 transcripts were significantly overexpressed in tamoxifen resistance patients. Immunohistochemical staining indicated that protein expression of P28GANK and Oct-4 were also significantly higher in tamoxifen resistance patients. We have shown a positive correlation between mRNA and protein expression of P28GANK, Oct-4 and Sox-2. Multivariate logistic regression analysis indicated that P28GANK (P = 0.002) and Oct-4 (P = 0.013) overexpression could be negative independent factors of disease outcome. Additionally, in the whole study group, multivariate Cox regression analysis revealed that high expression of P28GANK and Oct-4 remained significant and unfavorable predictive factors for patients’ survival. These findings suggest that Gankyrin and Oct-4 overexpression could promote tamoxifen refractory in breast cancer patients. More studies are warranted to clarify the predictive role of these potential biomarkers for patients who don’t benefit from tamoxifen treatment and their possible application as prognostic markers in ER⁺ tamoxifen-treated breast carcinoma patients.

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Johansson HJ, Sanchez BC, Mundt F, Forshed J, Kovacs A, Panizza E, Hultin-Rosenberg L, Lundgren B, Martens U, Mathe G, Yakhini Z, Helou K, Krawiec K, Kanter L, Hjerpe A, Stal O, Linderholm BK, Lehtio J (2013) Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer. Nat Commun 4:2175. https://doi.org/10.1038/ncomms3175 CrossRefPubMedPubMedCentral

Hayes EL, Lewis-Wambi JS (2015) Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA. Breast cancer research : BCR 17:40. https://doi.org/10.1186/s13058-015-0542-y CrossRefPubMed

Szostakowska M, Trębińska-Stryjewska A, Grzybowska EA, Fabisiewicz A (2019) Resistance to endocrine therapy in breast cancer: molecular mechanisms and future goals. 173 (3):489-497. https://doi.org/10.1007/s10549-018-5023-4

Kumar SM, Liu S, Lu H, Zhang H, Zhang PJ, Gimotty PA, Guerra M, Guo W, Xu X (2012) Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene 31(47):4898–4911 http://www.nature.com/onc/journal/v31/n47/suppinfo/onc2011656s1.html CrossRef

Yuan J, Liu M, Yang L, Tu G, Zhu Q, Chen M, Cheng H, Luo H, Fu W, Li Z, Yang G (2015) Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells. Breast Cancer Res 17(1):69. https://doi.org/10.1186/s13058-015-0579-y CrossRefPubMedPubMedCentral

Maynard PV, Blamey RW, Elston CW, Haybittle JL, Griffiths K (1978) estrogen receptor assay in primary breast cancer and early recurrence of the disease. Cancer Research 38 (11 Part 2):4292-4295

Simões BM, Piva M, Iriondo O, Comaills V, López-Ruiz JA, Zabalza I, Mieza JA, Acinas O, Vivanco MM (2011) Effects of estrogen on the proportion of stem cells in the breast. Breast Cancer Res Treat 129(1):23–35. https://doi.org/10.1007/s10549-010-1169-4 CrossRefPubMed

Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J (2000) Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 6(1):96–99. https://doi.org/10.1038/71600 CrossRefPubMed

Li H, Zhang J, Zhen C, Yang B, Feng L (2018) Gankyrin as a potential target for tumor therapy: evidence and perspectives. Am J Transl Res 10(7):1949–1960PubMedPubMedCentral

10.

Higashitsuji H, Higashitsuji H, Itoh K, Sakurai T, Nagao T, Sumitomo H, Masuda T, Dawson S, Shimada Y, Mayer RJ, Fujita J (2005) The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell 8(1):75–87. https://doi.org/10.1016/j.ccr.2005.06.006 CrossRefPubMed

11.

Mandlekar S, Kong AN (2001) Mechanisms of tamoxifen-induced apoptosis. Apoptosis: An International Journal on Programmed Cell Death 6(6):469–477CrossRef

12.

Gelmann EP (1996) Tamoxifen induction of apoptosis in estrogen receptor-negative cancers: new tricks for an old dog? J Natl Cancer Inst 88(5):224–226CrossRef

13.

Kim YH, Kim JH, Choi YW, Lim SK, Yim H, Kang SY, Chung YS, Lee GY, Park TJ (2013) Gankyrin is frequently overexpressed in breast cancer and is associated with ErbB2 expression. Exp Mol Pathol 94(2):360–365. https://doi.org/10.1016/j.yexmp.2012.12.002 CrossRefPubMed

14.

Mine H, Sakurai T, Kashida H, Matsui S, Nishida N, Nagai T, Hagiwara S, Watanabe T, Kudo M (2013) Association of gankyrin and stemness factor expression in human colorectal cancer. Dig Dis Sci 58(8):2337–2344. https://doi.org/10.1007/s10620-013-2627-8 CrossRefPubMed

15.

Jahangiri R, Mosaffa F, Emami Razavi A, Teimoori-Toolabi L, Jamialahmadi K (2018) Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors. J Cell Physiol 233(9):7305–7319. https://doi.org/10.1002/jcp.26562 CrossRefPubMed

16.

Wang H, Yang B, Geng T, Li B, Dai P, Chen C (2015) Tissue-specific selection of optimal reference genes for expression analysis of anti-cancer drug-related genes in tumor samples using quantitative real-time RT-PCR. Exp Mol Pathol 98(3):375–381. https://doi.org/10.1016/j.yexmp.2014.10.014 CrossRefPubMed

17.

Wang W-P, Sun Y, Lu Q, Zhao J-B, Wang X-J, Chen Z, Ni Y-F, Wang J-Z, Han Y, Zhang Z-P, Yan X-L, Li X-F (2016) Gankyrin promotes epithelial-mesenchymal transition and metastasis in NSCLC through forming a closed circle with IL-6/ STAT3 and TGF-β/SMAD3 signaling pathway. Oncotarget 8(4):5909–5923. https://doi.org/10.18632/oncotarget.13947 CrossRefPubMedCentral

18.

Mosaffa F, Kalalinia F, Lage H, Afshari JT, Behravan J (2012) Pro-inflammatory cytokines interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha alter the expression and function of ABCG2 in cervix and gastric cancer cells. Mol Cell Biochem 363(1):385–393. https://doi.org/10.1007/s11010-011-1191-9 CrossRefPubMed

19.

Jahangiri R, Mosaffa F, Gharib M, Emami Razavi AN, Abdirad A, Jamialahmadi K (2018) PAX2 expression is correlated with better survival in tamoxifen-treated breast carcinoma patients. Tissue Cell 52:135–142. https://doi.org/10.1016/j.tice.2018.05.005 CrossRefPubMed

20.

Amaya CN, Bryan BA (2015) Enrichment of the embryonic stem cell reprogramming factors Oct4, Nanog, Myc, and Sox2 in benign and malignant vascular tumors. BMC Clin Pathol 15:18. https://doi.org/10.1186/s12907-015-0018-0 CrossRefPubMedPubMedCentral

21.

Zeng YC, Sun D, Li WH, Zhao J, Xin Y (2017) Gankyrin promotes the proliferation of gastric cancer and is associated with chemosensitivity. Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine 39(6):1010428317704820. https://doi.org/10.1177/1010428317704820 CrossRef

22.

Tanic N, Milovanovic Z, Tanic N, Dzodic R, Juranic Z, Susnjar S, Plesinac-Karapandzic V, Tatic S, Dramicanin T, Davidovic R, Dimitrijevic B (2012) The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients. Cancer Biology & Therapy 13(12):1165–1174. https://doi.org/10.4161/cbt.21346 CrossRef

23.

Thrane S, Pedersen AM, Thomsen MBH, Kirkegaard T, Rasmussen BB, Duun-Henriksen AK, Lankholm AV, Bak M, Lykkesfeldt AE, Yde CW (2015) A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells. Oncogene 34(32):4199–4210. https://doi.org/10.1038/onc.2014.351 CrossRefPubMed

24.

Zamani P, Matbou Riahi M, Momtazi-Borojeni AA, Jamialahmadi K (2018) Gankyrin: a novel promising therapeutic target for hepatocellular carcinoma. Artificial Cells, Nanomedicine, and Biotechnology 46(7):1301–1313. https://doi.org/10.1080/21691401.2017.1388250 CrossRefPubMed

25.

Taheri M, Jamialahmadi K, Kalalinia F (2017) Unexpected Lower Expression of Oncoprotein Gankyrin in Drug Resistant ABCG2 Overexpressing Breast Cancer Cell Lines. Asian Pac J Cancer Prev 18(12):3413–3418. https://doi.org/10.22034/apjcp.2017.18.12.3413 CrossRefPubMedPubMedCentral

26.

Chen X, Zhang M, Liu LX (2009) The overexpression of multidrug resistance-associated proteins and gankyrin contribute to arsenic trioxide resistance in liver and gastric cancer cells. Oncol Rep 22(1):73–80CrossRef

27.

Qian YW, Chen Y, Yang W, Fu J, Cao J, Ren YB, Zhu JJ, Su B, Luo T, Zhao XF, Dai RY, Li JJ, Sun W, Wu MC, Feng GS, Wang HY (2012) p28(GANK) prevents degradation of Oct4 and promotes expansion of tumor-initiating cells in hepatocarcinogenesis. Gastroenterology 142(7):1547–1558. e1514. https://doi.org/10.1053/j.gastro.2012.02.042 CrossRefPubMed

28.

Sun J, Xu K, Qiu Y, Gao H, Xu J, Tang Q, Yin P (2017) Bufalin reverses acquired drug resistance by inhibiting stemness in colorectal cancer cells. Oncol Rep 38(3):1420–1430. https://doi.org/10.3892/or.2017.5826 CrossRefPubMedPubMedCentral

29.

Rodriguez D, Ramkairsingh M, Lin X, Kapoor A, Major P, Tang D (2019) The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer. Cancers 11(7). https://doi.org/10.3390/cancers11071028

30.

Arif K, Hussain I, Rea C, El-Sheemy M (2015) The role of Nanog expression in tamoxifen-resistant breast cancer cells. OncoTargets and Therapy 8:1327–1334. https://doi.org/10.2147/OTT.S67835 CrossRefPubMedPubMedCentral

31.

Leung EY, Askarian-Amiri ME, Sarkar D, Ferraro-Peyret C, Joseph WR, Finlay GJ, Baguley BC (2017) Endocrine Therapy of Estrogen Receptor-Positive Breast Cancer Cells: Early Differential Effects on Stem Cell Markers. Front Oncol 7:184. https://doi.org/10.3389/fonc.2017.00184 CrossRefPubMedPubMedCentral

32.

Zhong B, Lin Y, Lai Y, Zheng F, Zheng X, Huang R, Yang W, Chen Z (2016) Relationship of Oct-4 to malignant stage: a meta-analysis based on 502 positive/high Oct-4 cases and 522 negative/low case-free controls. Oncotarget 7(2):2143–2152. https://doi.org/10.18632/oncotarget.5737 CrossRefPubMed

33.

Zhao X, Liu F, Zhang Y, Li P (2016) Prognostic and clinicopathological significance of Gankyrin overexpression in cancers: evidence from a meta-analysis. Onco Targets Ther 9:1961–1968. https://doi.org/10.2147/OTT.S101687 CrossRefPubMedPubMedCentral

34.

Yang F, Zhang J, Yang H (2018) OCT4, SOX2, and NANOG positive expression correlates with poor differentiation, advanced disease stages, and worse overall survival in HER2(+) breast cancer patients. Onco Targets Ther 11:7873–7881. https://doi.org/10.2147/ott.s173522 CrossRefPubMedPubMedCentral

35.

Wilbertz T, Wagner P, Petersen K, Stiedl AC, Scheble VJ, Maier S, Reischl M, Mikut R, Altorki NK, Moch H, Fend F, Staebler A, Bass AJ, Meyerson M, Rubin MA, Soltermann A, Lengerke C, Perner S (2011) SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer. Modern pathology: an Official Journal of the United States and Canadian Academy of Pathology, Inc 24(7):944–953. https://doi.org/10.1038/modpathol.2011.49 CrossRef

36.

Yu B, Cai H, Xu Z, Xu T, Zou Q, Gu M (2016) Expressions of stem cell transcription factors Nanog and Oct4 in renal cell carcinoma tissues and clinical significance. Artificial Cells, Nanomedicine, and Biotechnology 44(8):1818–1823. https://doi.org/10.3109/21691401.2015.1105238 CrossRefPubMed

Title: Increased Expression of Gankyrin and Stemness Factor Oct-4 are Associated with Unfavorable Clinical Outcomes and Poor Benefit of Tamoxifen in Breast Carcinoma Patients
Authors: Rosa Jahangiri
Fatemeh Mosaffa
Amirnader EmamiRazavi
Masoumeh Gharib
Khadijeh Jamialahmadi
Publication date: 01-07-2020
Publisher: Springer Netherlands
Keywords: Breast Cancer
Breast Cancer
Tamoxifen
Published in: Pathology & Oncology Research / Issue 3/2020
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-019-00766-2

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