Meme kanseri hastalarında östrojen reseptörü ile YAP ifadesi arasındaki ilişki: bir meta-analiz çalışması

Yıl 2024, , 58 - 64, 31.05.2024

Özlem Erol

https://doi.org/10.55665/troiamedj.1455143

Öz

Amaç: Bu meta-analizde meme kanseri hastalarında östrojen reseptörü (ER) ile YAP protein ifadesi arasın-daki ilişkinin ortaya konulması amaçlanmıştır. YAP proteini, karsinogenez ile ilişkisi bilinen hippo sinyal yolunda efektör bir moleküldür. Mevcut kanıtlar meme kanserinde östrojen reseptörü ile YAP arasındaki ilişkiye dair çelişkiler içermektedir. Meme kanserinde östrojen reseptörü ile YAP ilişkisinin ortaya çıka-rılması YAP’ın rolünü ve terapötik hedef olma potansiyelini anlamaya katkı sağlayacaktır.
Yöntem: Bu çalışmada, birincil araştırmaların birlikte yorumlanmasına olanak veren meta-analiz yöntemi kullanıldı. Çalışmaya YAP ifadesinin immünohistokimyasal olarak belirlendiği dokuz tane birincil çalış-ma dâhil edildi.
Bulgular: Meme kanseri hastalarında yüksek YAP ifadesi ile ER negatifliği arasında anlamlı bir ilişkili olduğu belirlendi (OR=0,739, %95 CI=0,577-0,946, p=0,016). Alt grup analizleri ise, nüklear ve sitoplaz-mik YAP ifadesi ile ER arasında anlamlı bir ilişki olmadığını, hücre genelindeki yüksek YAP ifadesinin ise ER negatifliği ile anlamlı bir ilişkisi olduğunu gösterdi (OR=0,526, %95 CI=0,388-0,712, p=0,000).
Sonuç: YAP ile ER arasında belirlenen ilişki YAP’ın, ER+ tümörlerde daha düşük ifade ile tümör baskıla-yıcı rolünü, ER- tümörlerde ise yüksek ifade ile onkogenik rolünü destekler. Bizim verilerimiz ER- alt tiplerde YAP’ın terapötik potansiyeli olabileceğini destekler. Fakat bu meta-analizde, dahil edilen çalışma sayısının sınırlı olduğu, ağırlıklı olarak Güneydoğu Asya popülasyonuna ait verileri içerdiği ve çalışmala-rın metodolojik farklılıklarının önemli sınırlılığa neden olabileceği unutulmamalıdır.

Anahtar Kelimeler

Meme kanseri, Östrojen reseptörü, YAP

The relationship between estrogen receptor and YAP expression in breast cancer patients: a meta-analysis study

Öz

Objectives: This meta-analysis aimed to reveal the relationship between estrogen receptor (ER) and YAP protein expression in breast cancer patients. YAP protein is an effector molecule in the Hippo signaling pathway, which is known to be associated with carcinogenesis. Current evidence is conflicting regarding the relationship between estrogen receptor and YAP in breast cancer. Revealing the relationship between estrogen receptor and YAP expression in breast cancer will contribute to understanding the role of YAP and its potential as a therapeutic target.
Methods: In this study, the meta-analysis method was used, which allows primary studies to be interpre-ted together. Nine primary studies in which YAP expression was determined immunohistochemically were included in our study.
Results: A significant correlation was determined between high YAP expression and ER negativity in breast cancer patients (OR=0.739, 95% CI=0.577-0.946, p=0.016). Subgroup analyzes showed that there was no significant relationship between nuclear and cytoplasmic YAP expression and ER, while high YAP expression throughout the cell had a significant relationship with ER negativity (OR=0.526, 95% CI=0.388-0.712, p=0.000).
Conclusion: The determined relationship between YAP and ER supports the tumor suppressor role of YAP, with its lower expression in ER+ tumors, and its oncogenic role, with its high expression in ER- tumors. Our data support that YAP may have therapeutic potential in ER- subtypes. However, it should be noted that in this meta-analysis, the number of studies included was limited, mainly included data from the Southeast Asian population, and methodological differences of the studies may cause significant limitations.

Anahtar Kelimeler

Breast cancer, estrogen receptor, YAP

Etik Beyan

Yok

Destekleyen Kurum

Yok

Teşekkür

Yok

Kaynakça

• 1. Global breast cancer initiative implementa-tion framework: assessing, strengthening and scaling up of services for the early detection and management of breast cancer. Geneva: World Health Organization, 2023.
• 2. Kunheri B, Raj RV, Vijaykumar DK, Pavith-ran K. Impact of St. Gallen surrogate classifi-cation for intrinsic breast cancer sub-types on disease features, recurrence, and survival in South Indian patients. Indian J Cancer. 2020; 57(1):49-54.
• 3. Fu M, Hu Y, Lan T, Guan KL, Luo T, Luo M. Correction: The Hippo signalling pathway and its implications in human health and di-seases. Signal Transduct Target Ther. 2024; 9(1):5.
• 4. Cunningham R, Hansen CG. The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin Sci (Lond). 2022; 136(3):197-222.
• 5. Kwon Y, Vinayagam A, Sun X, Dephoure N, Gygi SP, Hong P, Perrimon N. The Hippo sig-naling pathway interactome. Science. 2013; 342(6159):737-740.
• 6. Luo J, Zou H, Guo Y, Tong T, Chen Y, Xiao Y, Pan Y, Li P. The oncogenic roles and clini-cal implications of YAP/TAZ in breast can-cer. Br J Cancer. 2023; 128(9):1611-1624.
• 7. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, Deng CX, Brugge JS, Haber DA. Transforming properties of YAP, a can-didate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA. 2006; 103(33):12405-12410.
• 8. Zhao Y, Sheldon M, Sun Y, Ma L. New In-sights into YAP/TAZ-TEAD-mediated gene regulation and biological processes in cancer. Cancers (Basel). 2023; 15(23):5497.
• 9. Panciera T, Citron A, Di Biagio D, et al. Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated chan-ges of cell mechanical properties. Nat Mater. 2020; 19(4):475.
• 10. Vlahov N, Scrace S, Soto MS, Grawenda AM, Bradley L, Pankova D, Papaspyropoulos A, Yee KS, Buffa F, Goding CR, Timpson P, Sib-son N, O'Neill E. Alternate RASSF1 transc-ripts control SRC activity, e-cadherin con-tacts, and YAP-mediated invasion. Curr Biol. 2015; 25(23):3019-3034.
• 11. Yousefi H, Delavar MR, Piroozian F, Baghi M, Nguyen K, Cheng T, Vittori C, Worthyla-ke D, Alahari SK. Hippo signaling pathway: A comprehensive gene expression profile analysis in breast cancer. Biomed Pharmacot-her. 2022; 151:113144.
• 12. Raj N, Bam R. Reciprocal crosstalk between YAP1/hippo pathway and the p53 family proteins: Mechanisms and outcomes in can-cer. Front Cell Dev Biol. 2019; 7:159.
• 13. Levy D, Adamovich Y, Reuven N, Shaul Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol Cell. 2008; 29(3):350-361.
• 14. Gu G, Dustin D, Fuqua SA. Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment. Curr Opin Pharma-col. 2016; 31:97-103.
• 15. Hou L, Xie S, Li G, Xiong B, Gao Y, Zhao X, Hu J, Deng S, Jiang J. IL-6 triggers the migra-tion and invasion of oestrogen receptor-negative breast cancer cells via regulation of hippo pathways. Basic Clin Pharmacol Toxi-col. 2018; 123(5):549-557.
• 16. Ma S, Tang T, Probst G, Konradi A, Jin C, Li F, Gutkind JS, Fu XD, Guan KL. Transcripti-onal repression of estrogen receptor alpha by YAP reveals the hippo pathway as therapeu-tic target for ER+ breast cancer. Nat Commun. 2022; 13(1):1061.
• 17. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003; 327(7414):557-560.
• 18. Sheen-Chen SM, Huang CY, Tsai CH, Liu YW, Wu SC, Huang CC, Eng HL, Chan YC, Ko SF, Tang RP. Yes-associated protein is not an independent prognostic marker in bre-ast cancer. Anticancer Res. 2012; 32(8):3321-3325.
• 19. Kim SK, Jung WH, Koo JS. Yes-associated protein (YAP) is differentially expressed in tumor and stroma according to the molecular subtype of breast cancer. Int J Clin Exp Pat-hol. 2014; 7(6):3224-3234.
• 20. Lehn S, Tobin NP, Sims AH, Stål O, Jirström K, Axelson H, Landberg G. Decreased expression of Yes-associated protein is asso-ciated with outcome in the luminal A breast cancer subgroup and with an impaired ta-moxifen response. BMC Cancer. 2014; 22(14):119.
• 21. Cao L, Sun PL, Yao M, Jia M, Gao H. Expres-sion of YES-associated protein (YAP) and its clinical significance in breast cancer tis-sues. Hum Pathol. 2017; 68:166-174.
• 22. Ding N, Huang T, Yuan J, Mao J, Duan Y, Liao W, Xiao Z. Yes-associated protein expression in paired primary and local recur-rent breast cancer and its clinical significan-ce. Curr Probl Cancer. 2019; 43(5):429-437.
• 23. Kalita-de Croft P, Lim M, Chittoory H, de Luca XM, Kutasovic JR, Day BW, Al-Ejeh F, Simpson PT, McCart Reed AE, Lakhani SR, Saunus JM. Clinicopathologic significance of nuclear HER4 and phospho-YAP(S127) in human breast cancers and matching brain me-tastases. Ther Adv Med Oncol. 2020; 12:1758835920946259.
• 24. Cha YJ, Kim D, Bae SJ, Ahn SG, Jeong J, Cho MK, Paik PS, Yoo TK, Park WC, Yoon CI. The association between the expression of nuclear yes-associated protein 1 (YAP1) and p53 protein expression profile in breast can-cer patients. PLoS One. 2021; 16(5):e0250986.
• 25. Liu P, Zeng J, Yang G. Expression of yes-associated protein, β-catenin and smoothe-ned, and their clinical significance in invasi-ve breast cancer. Exp Ther Med. 2022; 23(6):429.
• 26. Li X, Zhuo S, Zhuang T, Cho YS, Wu G, Liu Y, Mu K, Zhang K, Su P, Yang Y, Zhang CC, Zhu J, Jiang J. YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis. Nat Commun. 2022; 13(1):3075.
• 27. Cooper H, Hedges LV, Valentine, JC. The Handbook of Research Synthesis and Meta-analysis. 2nd ed. New York: Russell Sage Publication; 2009.
• 28. Li L, Luo J, Fang JY, Zhang R, Ma JB, Zhu ZP. Expression characteristics of the yes-associated protein in breast cancer: A meta-analysis. Medicine (Baltimore). 2022; 101(34):e30176.
• 29. Venkatasubramanian G, Kelkar DA, Mandal S, Jolly MK, Kulkarni M. Analysis of Yes-associated protein-1 (YAP1) target gene sig-nature to predict progressive breast cancer. J Clin Med. 2022; 11(7):1947.