The Relationship between the Levels of SIAH1, BIM and p53 Proteins in association with the Disease Course in Patients with Breast Cancer

Öz

Cancer is one of the most significant health issues worldwide, and breast cancer is among the most common types. Despite advancements in treatment methods, breast cancer remains difficult to treat effectively. Therefore, identifying new biomarkers for the diagnosis and treatment of breast cancer is of great interest. The SIAH1 (Seven in absentia homolog 1) protein is recognized as a tumor suppressor. Although studies have demonstrated its crucial roles in cancer processes, its potential in breast cancer diagnosis and treatment has not been fully explored. Previous research has shown that SIAH1 is linked with important tumor suppressor and apoptosis-inducing proteins such as p53 and BIM. In this thesis, we used immunohistochemical methods to investigate the relationship between the levels of SIAH1, BIM, and p53 proteins, which play key roles in the prognosis and apoptosis processes in breast cancer patients. Our results showed that the level of SIAH1 protein was significantly reduced in the tumor tissues of breast cancer patients. In contrast, there was no significant difference in the expression level of BIM. Additionally, p53 was not detected in 75% of the breast cancer patients, but in the remaining 25%, p53 expression was significantly increased. Our study also indicated that low SIAH1 expression levels are associated with important clinical characteristics such as tumor grade, stage, and breast cancer type. These findings suggest that SIAH1 plays a role in breast cancer formation and could be a novel biomarker for the diagnosis and treatment of breast cancer.

Anahtar Kelimeler

• Apoptosis
• BIM
• Breast Cancer
• Immunohistochemistry
• SIAH1
• p53

Meme Kanser Hastalarının Tedavi Seyri ile SIAH, BIM VE P53 Proteinlerin Seviyeleri Arasındaki İlişkinin İmmunohistokimyasal Olarak Ortaya Konulması

Öz

Kanser, dünya genelinde en önemli sağlık sorunlarından biridir ve meme kanseri en yaygın türler arasında yer almaktadır. Tedavi yöntemlerindeki ilerlemelere rağmen, meme kanserinin etkili bir şekilde tedavi edilmesi hâlâ zorluklar içermektedir. Bu nedenle, meme kanserinin tanı ve tedavisi için yeni biyobelirteçlerin belirlenmesi büyük ilgi görmektedir. SIAH1 (Seven in absentia homolog 1) proteini, bir tümör baskılayıcı olarak tanınmaktadır. Yapılan çalışmalar, bu proteinin kanser süreçlerinde kritik roller üstlendiğini göstermiştir; ancak meme kanserinin tanı ve tedavisindeki potansiyeli tam olarak araştırılmamıştır. Önceki araştırmalar, SIAH1’in p53 ve BIM gibi önemli tümör baskılayıcı ve apoptozu indükleyen proteinlerle ilişkili olduğunu ortaya koymuştur. Bu tezde, meme kanseri hastalarında prognoz ve apoptoz süreçlerinde kilit rol oynayan SIAH1, BIM ve p53 proteinlerinin düzeyleri arasındaki ilişkiyi immünhistokimyasal yöntemlerle araştırdık. Bulgularımız, meme kanseri hastalarının tümör dokularında SIAH1 protein düzeyinin anlamlı şekilde azaldığını göstermiştir. Buna karşılık, BIM ifadesinde anlamlı bir fark gözlenmemiştir. Ayrıca, meme kanseri hastalarının %75’inde p53 tespit edilmemiştir; ancak kalan %25’lik kesimde p53 ifadesi anlamlı şekilde artmıştır. Çalışmamız ayrıca düşük SIAH1 ekspresyon düzeylerinin tümör derecesi, evresi ve meme kanseri tipi gibi önemli klinik özelliklerle ilişkili olduğunu göstermiştir. Bu bulgular, SIAH1’in meme kanseri oluşumunda rol oynadığını ve bu hastalığın tanı ve tedavisinde yeni bir biyobelirteç olabileceğini düşündürmektedir.

Anahtar Kelimeler

• Apoptoz
• BIM
• meme kanseri
• immünohistokimya
• Siah1
• p53

Kaynakça

1. 1. Anand U, Dey A, Chandel AKS, Sanyal R, Mishra A, Pandey DK, et al. Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics. 2022.
2. 2. Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, et al. Breast cancer: Biology, biomarkers, and treatments. L.T.H. Alsaleem Agha 2020;84:106535.
3. 3. Basu A, Ramamoorthi G, Jia Y, Faughn J, Wiener D, Awshah S, et al. Immunotherapy in breast cancer: Current status and future directions. 2019;143:295-349.
4. 4. Campbell C, Quinn AG, Ro Y-S, Angus B, Rees JLJJoid. p53 mutations are common and early events that precede tumor invasion in squamous cell neoplasia of the skin. 1993;100(6):746-8.
5. 5. da Silva JL, Nunes NCC, Izetti P, de Mesquita GG, de Melo ACJCrioh. Triple negative breast cancer: A thorough review of biomarkers. 2020;145:102855.
6. 6. Eoh KJ, Kim HM, Lee J-Y, Kim S, Kim SW, Kim YT, et al. Mutation landscape of germline and somatic BRCA1/2 in patients with high-grade serous ovarian cancer. 2020;20:1-8.
7. 7. Evans DG, Woodward ER, Bajalica-Lagercrantz S, Oliveira C, Frebourg TJC. Germline TP53 testing in breast cancers: Why, when and how? 2020;12(12):3762.
8. 8. Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, et al. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. 2011;1(4):352-65.

9. 9. García-Aranda M, Redondo MJC. Immunotherapy: a challenge of breast cancer treatment. 2019;11(12):1822. 10. Gasco M, Shami S, Crook TJBcr. The p53 pathway in breast cancer. 2002;4:1-7.
10. 11. Gottlieb TM, Oren MJBeBA-RoC. p53 in growth control and neoplasia. 1996;1287(2-3):77-102.
11. 12. Grishina I, Debus K, García-Limones C, Schneider C, Shresta A, García C, et al. SIAH-mediated ubiquitination and degradation of acetyltransferases regulate the p53 response and protein acetylation. 2012;1823(12):2287-96.
12. 13. Grote I, Bartels S, Kandt L, Bollmann L, Christgen H, Gronewold M, et al. TP53 mutations are associated with primary endocrine resistance in luminal early breast cancer. 2021;10(23):8581-94.
13. 14. Gu G, Dustin D, Fuqua SAJCoip. Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment. 2016;31:97-103.
14. 15. Guo Z, Song T, Wang Z, Lin D, Cao K, Liu P, et al. The chaperone Hsp70 is a BH3 receptor activated by the pro-apoptotic Bim to stabilize antiapoptotic clients. 2020;295(37):12900-9.
15. 16. Hafner A, Bulyk ML, Jambhekar A, Lahav GJNrMcb. The multiple mechanisms that regulate p53 activity and cell fate. 2019;20(4):199-210.
16. 17. He H-T, Fokas E, You A, Engenhart-Cabillic R, An H-XJBc. Siah1 proteins enhance radiosensitivity of human breast cancer cells. 2010;10:1-11.
17. 18. Hisada M, Garber JE, Li FP, Fung CY, Fraumeni JFJJJotNCI. Multiple primary cancers in families with Li-Fraumeni syndrome. 1998;90(8):606-11.
18. 19. Hussain SP, Harris CCJMRRiMR. Molecular epidemiology and carcinogenesis: endogenous and exogenous carcinogens. 2000;462(2-3):311-22.
19. 20. Jassim MMA, Rasool KH, Mahmood MMJVW. p53, p21, and cyclin d1 protein expression patterns in patients with breast cancer. 2021;14(10):2833.
20. 21. Kesteloot HE, Zhang JJEjocp. Differences in breast cancer mortality worldwide: unsolved problems. 2006;15(5):416-23. 22. Lacroix M, Toillon R-A, Leclercq GJE-rc. p53 and breast cancer, an update. 2006;13(2):293-325.
21. 23. Liu R, Yu X, Chen X, Zhong H, Liang C, Xu X, et al. Individual factors define the overall effects of dietary genistein exposure on breast cancer patients. Nutrition research (New York, NY). 2019;67:1-16.
22. 24. Liu Z, Luo P, Cao K, Hu Q, Hu B, Cui L, et al. SIAH1/CTR9 axis promotes the epithelial–mesenchymal transition of hepatocellular carcinoma. 2023;44(4):304-16.
23. 25. Luo D, Yu C, Yu J, Su C, Li S, Liang P. p53- mediated G1 arrest requires the induction of both p21 and Killin in human colon cancer cells. Cell L.T.H. Alsaleem Agha cycle (Georgetown, Tex). 2022;21(2):140-51.
24. 26. Maimaiti Y, Dong L, Aili A, Maimaitiaili M, Huang T, Abudureyimu KJCB. BIM may be a poor prognostic biomarker in breast cancer patients especially in those with luminal A tumors. 2017;19(4):411-8.
25. 27. Meek DWJBJ. Regulation of the p53 response and its relationship to cancer. 2015;469(3):325-46.
26. 28. Merino D, Best SA, Asselin-Labat M-L, Vaillant F, Pal B, Dickins RA, et al. Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2. 2015;34(30):3926-34.
27. 29. Mirzayans R, Andrais B, Scott A, Murray DJBRI. New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. 2012;2012.
28. 30. Nedeljković M, Damjanović AJC. Mechanisms of chemotherapy resistance in triple-negative breast cancer—how we can rise to the challenge.2019;8(9):957.
29. 31. Park HY, Park S-H, Jeong J-W, Yoon D, Han MH, Lee D-S, et al. Induction of p53-independent apoptosis and G1 cell cycle arrest by fucoidan in HCT116 human colorectal carcinoma cells. 2017;15(6):154.
30. 32. Peleg Hasson S, Menes T, Sonnenblick AJP, Medicine P. Comparison of patient susceptibility genes across breast cancer: implications for prognosis and therapeutic outcomes. 2020:227-38.
31. 33. Pharoah P, Day N, Caldas CJBjoc. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. 1999;80(12):1968-73.
32. 34. Polyak KJTJoci. Heterogeneity in breast cancer. 2011;121(10):3786-8.
33. 35. Prives C, Hall PAJTJop. The p53 pathway. 1999;187(1):112-26.
34. 36. Relaix F, Wei X-j, Li W, Pan J, Lin Y, Bowtell DD, et al. Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. 2000;97(5):2105-10.
35. 37. Roperch JP, Lethrone F, Prieur S, Piouffre L, Israeli D, Tuynder M, et al. SIAH-1 promotes apoptosis and tumor suppression through a network involving the regulation of protein folding, unfolding, and trafficking: identification of common effectors with p53 and p21(Waf1). Proceedings of the National Academy of Sciences of the United States of America. 1999;96(14):8070-3.
36. 38. Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. 2003;8(4):307-25.
37. 39. Shahbandi A, Nguyen HD, Jackson JGJTic. TP53 mutations and outcomes in breast cancer: reading beyond the headlines. 2020;6(2):98-110.
38. 40. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: a cancer journal for clinicians. 2023;73(1):17-48.
39. 41. Sionov RV, Haupt YJO. The cellular response to p53: the decision between life and death. 1999;18(45):6145-57.
40. 42. van der Willik KD, Timmermans MM, van Deurzen CH, Look MP, Reijm EA, van Zundert WJ, et al. SIAH2 protein expression in breast cancer is inversely related with ER status and outcome to tamoxifen therapy. 2016;6(2):270.
41. 43. Vitto VAM, Bianchin S, Zolondick AA, Pellielo G, Rimessi A, Chianese D, et al. Molecular mechanisms of autophagy in cancer development, progression, and therapy. 2022;10(7):1596.
42. 44. Wahba J, Natoli M, Whilding LM, Parente-Pereira AC, Jung Y, Zona S, et al. Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer. 2018;67:1753-65.
43. 45. Wen YY, Yang ZQ, Song M, Li BL, Yao XH, Chen XL, et al. The expression of SIAH1 is downregulated and associated with Bim and apoptosis in human breast cancer tissues and cells. L.T.H. Alsaleem Agha 2010;49(5):440-9.
44. 46. Wen YY, Yang ZQ, Song M, Li BL, Zhu JJ, Wang EHJCs. SIAH1 induced apoptosis by activation of the JNK pathway and inhibited invasion by inactivation of the ERK pathway in breast cancer cells. 2010;101(1):73-9.
45. 47. Wichmann J, Pitt C, Eccles S, Garnham AL, Li-Wai-Suen CS, May R, et al. Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest. 2022;13(7):627.
46. 48. Yuan F, Chen X, Liu J, Feng W, Wu X, Chen SY. Up-regulation of Siah1 by ethanol triggers apoptosis in neural crest cells through p38 MAPKmediated activation of p53 signaling pathway. Archives of toxicology. 2017;91(2):775-84.
47. 49. Zhang C, Liu Z, Wang X, Zhang B, Cui L, Hu Q, et al. Cathepsin K promotes the proliferation of hepatocellular carcinoma cells through induction of SIAH1 ubiquitination and degradation. 2023;26(6).
48. 50. Zhang H, Wang J, Ge Y, Ye M, Jin XJOR. Siah1 in cancer and nervous system diseases. 2022;47(2):1-14.