Volume 27, Issue 2 And 3 (3-2023)                   IBJ 2023, 27(2 And 3): 126-135 | Back to browse issues page

PMID: 37070675

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Background: K-Ras mutations rarely occur in breast cancer. However, studies have supported that K-Ras upregulation is involved in breast cancer pathogenesis. Two main K-Ras transcript variants; K-Ras4A and K-Ras4B, originate from the alternative splicing of exon 4. In this study, we aimed to evaluate variations in the expression of K-Ras4A and K-Ras4B and their role in breast ductal carcinoma.
Methods: Total RNA was extracted from breast tumors, and the NATs obtained via mastectomy. Patients were selected from new cases of breast cancer with no prior history of chemotherapy. Relative mRNA expression was calculated based on a pairwise comparison between the tumors and the NATs following normalization to the internal control gene. Predictive values of the transcript variants were examined by ROC curve analysis.
Results: A statistically significant increase was found in the K-Ras4A and K-Ras4B expression with the mean fold changes of 7.58 (p = 0.01) and 2.47 (p = 0.001), respectively. The K-Ras4A/K-Ras4B ratio was lower in the tumors than that of the normal tissues. ROC curve analysis revealed the potential of K-Ras4A (AUC: 0.769) and K-Ras4B (AUC: 0.688) in breast cancer prediction. There was also a significant association between K-Ras4B expression and HER2 statues (p = 0.04). Furthermore, a significant link was detected between K-Ras4A expression and pathological prognostic stages (p = 0.04).
Conclusion: Our findings revealed that expression levels of K-Ras4A and K-Ras4B is higher in the tumor compared to the normal breast tissues. Increase in K-Ras4A expression was more significant than that of K-Ras4B.
Type of Study: Full Length/Original Article | Subject: Related Fields

1. Roshandel G, Ghanbari-Motlagh A, Partovipour E, Salavati F, Hasanpour-Heidari S, Mohammadi G, Khoshaabi M, Sadjadi A, Davanlou M, Tavangar SM, Abadi H, Asgari A, Behrooz M, Cheraghi M, Danechin L, Dolatkhah R, Enferadi F, Esshaghi S, Farahani M, Farrokhzad S, Fateh M, Vahedi S, Golpazir A, Hasanzadeh M, Hazar N, Hoseini-Hoshyar H, Izadi M, Jafarnia A, Jahantigh M, Jalilvand A, Jazayeri M, Joola P, Kazemzadeh Y, Khalednejad M, Kooshki M, Madani A, Malekpour-Afshar R, Bayat AH, Moinfar Z, Mohamadifar H, Mohamadzadeh G, Motidost-Komleh R, Narooei M, Niksiar S, Pirnejad H, Poornajaf A, Pourshahi G, Rahnama A, Rashidpour B, Ravankhah Z, Rezaei K, Rezaeianzadeh A, Sadeghi G, Shahdadi A, Shahi M, Sharafi Z, Sharifi-Moghadam F, Soleimani A, Soltany-Hojatabad M, Tahmasebi Z, Yadolahi S, Yaghoubi-Ashrafi M, Zandian H, Zareiyan A, Poustchi H, Zendehdel K, Ostovar A, Janbabaei G, Reisi AMalekzadeh R. Cancer incidence in Iran in 2014: Results of the Iranian National Population-based Cancer Registry. Cancer epidemiology 2019; 61: 50-58. [DOI:10.1016/j.canep.2019.05.009]
2. Duncan MALautner MA. Sarcomas of the Breast. Surgical clinics of North America 2018; 98(4): 869-876. [DOI:10.1016/j.suc.2018.03.013]
3. Dalenc F, Lusque A, De La Motte Rouge T, Pistilli B, Brain E, Pasquier D, Debled M, Thery JC, Gonçalves A, Desmoulins I, Levy C, Uwer L, Ferrero JM, Eymard JC, Mouret-Reynier MA, Patsouris A, Frenel JS, Petit T, Chevrot M, Bachelot TGuiu S. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. European journal of cancer 2022; 164: 70-79. [DOI:10.1016/j.ejca.2021.12.031]
4. Ali ES, Akter S, Ramproshad S, Mondal B, Riaz TA, Islam MT, Khan IN, Docea AO, Calina D, Sharifi-Rad JCho WC. Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview. Cancer cell international 2022; 22(1): 246. [DOI:10.1186/s12935-022-02666-z]
5. Chung CChristianson M. Predictive and prognostic biomarkers with therapeutic targets in breast, colorectal, and non-small cell lung cancers: a systemic review of current development, evidence, and recommendation. Journal of oncology pharmacy practice 2014; 20(1): 11-28. [DOI:10.1177/1078155212474047]
6. Tilch E, Seidens T, Cocciardi S, Reid LE, Byrne D, Simpson PT, Vargas AC, Cummings MC, Fox SB, Lakhani SRChenevix Trench G. Mutations in EGFR, BRAF and RAS are rare in triple-negative and basal-like breast cancers from Caucasian women. Breast cancer research and treatment 2014; 143(2): 385-392. [DOI:10.1007/s10549-013-2798-1]
7. Dunnett-Kane V, Burkitt-Wright E, Blackhall FH, Malliri A, Evans DGLindsay CR. Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts. Annals of oncology 2020; 31(7): 873-883. [DOI:10.1016/j.annonc.2020.03.291]
8. Nussinov R, Tsai CJ, Chakrabarti MJang H. A New View of Ras Isoforms in Cancers. Cancer research 2016; 76(1): 18-23. [DOI:10.1158/0008-5472.CAN-15-1536]
9. Laude AJPrior IA. Palmitoylation and localisation of RAS isoforms are modulated by the hypervariable linker domain. J Cell Sci 2008; 121(Pt 4): 421-427. [DOI:10.1242/jcs.020107]
10. Nussinov R, Muratcioglu S, Tsai CJ, Jang H, Gursoy AKeskin O. The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas. Molecular cancer research 2015; 13(9): 1265-1273. [DOI:10.1158/1541-7786.MCR-15-0165]
11. Pin-Joe K, Dixon SJ. Protein palmitoylation and cancer. EMBO reports 2018; 19(10): e46666. [DOI:10.15252/embr.201846666]
12. Wright LPPhilips MR. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. Journal of lipid reseach 2006; 47(5): 883-91. [DOI:10.1194/jlr.R600004-JLR200]
13. Zolfaghari N, Shahbazi S, Torfeh M, Khorasani M, Hashemi MMahdian R. Identification of Differentially Expressed K-Ras Transcript Variants in Patients With Leiomyoma. Reproductive sciences 2017; 24(10): 1438-1443. [DOI:10.1177/1933719116689596]
14. Mohamadalizadeh-Hanjani Z, Shahbazi SGeranpayeh L. Investigation of the SPAG5 gene expression and amplification related to the NuMA mRNA levels in breast ductal carcinoma. World journal of surgical oncology 2020; 18(1): 225. [DOI:10.1186/s12957-020-02001-8]
15. Tsai FD, Lopes MS, Zhou M, Court H, Ponce O, Fiordalisi JJ, Gierut JJ, Cox AD, Haigis KMPhilips MR. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proceedings of the national academy of sciences of the United States of America 2015; 112(3): 779-84. [DOI:10.1073/pnas.1412811112]
16. Aran V, Masson Domingues P, Carvalho de Macedo F, Moreira de Sousa CA, Caldas Montella T, de Souza Accioly MTFerreira CG. A cross-sectional study examining the expression of splice variants K-RAS4A and K-RAS4B in advanced non-small-cell lung cancer patients. Lung cancer 2018; 116: 7-14. [DOI:10.1016/j.lungcan.2017.12.005]
17. Shahrabi-Farahani M, Shahbazi S, Mahdian RAmini-Moghaddam S. K-Ras 4A Transcript variant is up-regulated in eutopic endometrium of endometriosis patients during proliferative phase of menstrual cycle. Archives of gynecology and obstetrics 2015; 292(1): 225-229. [DOI:10.1007/s00404-014-3596-7]
18. Giuliano AE, Edge SBHortobagyi GN. Eighth Edition of the AJCC Cancer Staging Manual: Breast Cancer. Annals of surgical oncology 2018; 25(7): 1783-1785. [DOI:10.1245/s10434-018-6486-6]
19. Patek CE, Arends MJ, Wallace WA, Luo F, Hagan S, Brownstein DG, Rose L, Devenney PS, Walker M, Plowman SJ, Berry RL, Kolch W, Sansom OJ, Harrison DJHooper ML. Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis. Experimental cell research 2008; 314(5): 1105-11014. [DOI:10.1016/j.yexcr.2007.11.004]
20. Plowman SJ, Arends MJ, Brownstein DG, Luo F, Devenney PS, Rose L, Ritchie AM, Berry RL, Harrison DJ, Hooper MLPatek CE. The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan
21. or spontaneous tumor incidence in aging mice. Experimental cell research 2006; 312(1): 16-26. [DOI:10.1016/j.yexcr.2005.10.004]
22. Luo F, Ye H, Hamoudi R, Dong G, Zhang W, Patek CE, Poulogiannis GArends MJ. K-ras exon 4A has a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation. Journal of pathology 2010; 220(5): 542-50. [DOI:10.1002/path.2672]
23. Plowman SJ, Berry RL, Bader SA, Luo F, Arends MJ, Harrison DJ, Hooper MLPatek CE. K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. Journal of expermental clinical cancer research 2006; 25(2): 259-267.
24. Riffo-Campos AL, Gimeno-Valiente F, Rodriguez FM, Cervantes A, Lopez-Rodas G, Franco LCastillo J. Role of epigenetic factors in the selection of the alternative splicing isoforms of human KRAS in colorectal cancer cell lines. Oncotarget 2018; 9(29): 20578-20589. [DOI:10.18632/oncotarget.25016]
25. Hwang KT, Kim BH, Oh S, Park SY, Jung J, Kim J, Choi IS, Jeon SYKim WY. Prognostic Role of KRAS mRNA Expression in Breast Cancer. Journal of breast cancer 2019; 22(4): 548-561. [DOI:10.4048/jbc.2019.22.e55]
26. Liang H, Zhou G, Lv L, Lu J, Peng J. KRAS expression is a prognostic indicator and associated with immune infiltration in breast cancer. Breast Cancer 2021; 28(2): 379-386. [DOI:10.1007/s12282-020-01170-4]

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