Differential impact of cytoplasmic vs. nuclear RAD51 expression on breast cancer progression and patient prognosis

Wang,Yen-Yun; Wang,Yen-Yun; Cheng,Kuang-Hung; Cheng,Kuang-Hung; Hung,Amos C.; Hung,Amos C.; Lo,Steven; Lo,Steven; Chen,Pang-Yu; Chen,Pang-Yu; Wu,Yi-Chia; Wu,Yi-Chia; Hou,Ming-Feng; Hou,Ming-Feng; Yuan,Shyng-Shiou F.; Yuan,Shyng-Shiou F.

doi:10.3892/ijo.2023.5600

Differential impact of cytoplasmic vs. nuclear RAD51 expression on breast cancer progression and patient prognosis

Authors:
- Yen-Yun Wang
- Kuang-Hung Cheng
- Amos C. Hung
- Steven Lo
- Pang-Yu Chen
- Yi-Chia Wu
- Ming-Feng Hou
- Shyng-Shiou F. Yuan
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Affiliations: School of Dentistry, College of Dental Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C., Institute of Biomedical Sciences, National Sun Yat‑Sen University, Kaohsiung 804, Taiwan, R.O.C., Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C., College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK, Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C., Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C., Drug Development and Value Creation Research Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
Published online on: December 7, 2023 https://doi.org/10.3892/ijo.2023.5600
Article Number: 12
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

RAD51 recombinase is one of the DNA damage repair proteins associated with breast cancer risk. Apart from its function to maintain genomic integrity within the cell nucleus, RAD51 localized to the cytoplasm has also been implicated in breast malignancy. However, limited information exists on the roles of cytoplasmic vs. nuclear RAD51 in breast cancer progression and patient prognosis. In the present study, the association of cytoplasmic and nuclear RAD51 with clinical outcomes of patients with breast cancer was analyzed, revealing that elevated cytoplasmic RAD51 expression was associated with breast cancer progression, including increased cancer stage, grade, tumor size, lymph node metastasis and chemoresistance, along with reduced patient survival. By contrast, elevated nuclear RAD51 expression largely had the inverse effect. Results from in vitro investigations supported the cancer‑promoting effect of RAD51, showing that overexpression of RAD51 promoted breast cancer cell growth, chemoresistance and metastatic ability, while knockdown of RAD51 repressed these malignant behaviors. The current data suggest that differential expression of subcellular RAD51 had a distinct impact on breast cancer progression and patient survival. Specifically, cytoplasmic RAD51 in contrast to nuclear RAD51 was potentially an adverse marker in breast cancer.

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Moo TA, Sanford R, Dang C and Morrow M: Overview of breast cancer therapy. PET Clin. 13:339–354. 2018. View Article : Google Scholar : PubMed/NCBI
3	Trayes KP and Cokenakes SEH: Breast cancer treatment. Am Fam Physician. 104:171–178. 2021.PubMed/NCBI
4	Martinez-Perez C, Turnbull AK, Ekatah GE, Arthur LM, Sims AH, Thomas JS and Dixon JM: Current treatment trends and the need for better predictive tools in the management of ductal carcinoma in situ of the breast. Cancer Treat Rev. 55:163–172. 2017. View Article : Google Scholar : PubMed/NCBI
5	Fahad Ullah M: Breast cancer: Current perspectives on the disease status. Adv Exp Med Biol. 1152:51–64. 2019. View Article : Google Scholar
6	Giridhar KV and Liu MC: Available and emerging molecular markers in the clinical management of breast cancer. Expert Rev Mol Diagn. 19:919–928. 2019. View Article : Google Scholar : PubMed/NCBI
7	Nickoloff JA: Targeting replication stress response pathways to enhance genotoxic chemo- and radiotherapy. Molecules. 27:47362022. View Article : Google Scholar : PubMed/NCBI
8	Wang Z, Jia R, Wang L, Yang Q, Hu X, Fu Q, Zhang X, Li W and Ren Y: The emerging roles of Rad51 in cancer and its potential as a therapeutic target. Front Oncol. 12:9355932022. View Article : Google Scholar : PubMed/NCBI
9	Lee MG, Lee KS and Nam KS: The association of changes in RAD51 and survivin expression levels with the proton beam sensitivity of Capan-1 and Panc-1 human pancreatic cancer cells. Int J Oncol. 54:744–752. 2019.
10	Connell PP, Jayathilaka K, Haraf DJ, Weichselbaum RR, Vokes EE and Lingen MW: Pilot study examining tumor expression of RAD51 and clinical outcomes in human head cancers. Int J Oncol. 28:1113–1119. 2006.PubMed/NCBI
11	Luzhna L, Golubov A, Ilnytskyy S, Chekhun VF and Kovalchuk O: Molecular mechanisms of radiation resistance in doxorubicin-resistant breast adenocarcinoma cells. Int J Oncol. 42:1692–1708. 2013. View Article : Google Scholar : PubMed/NCBI
12	Maacke H, Opitz S, Jost K, Hamdorf W, Henning W, Krüger S, Feller AC, Lopens A, Diedrich K, Schwinger E and Stürzbecher HW: Over-expression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer. Int J Cancer. 88:907–913. 2000. View Article : Google Scholar : PubMed/NCBI
13	Hu J, Wang N and Wang YJ: XRCC3 and RAD51 expression are associated with clinical factors in breast cancer. PLoS One. 8:e721042013. View Article : Google Scholar : PubMed/NCBI
14	Wiegmans AP, Al-Ejeh F, Chee N, Yap PY, Gorski JJ, Da Silva L, Bolderson E, Chenevix-Trench G, Anderson R, Simpson PT, et al: Rad51 supports triple negative breast cancer metastasis. Oncotarget. 5:3261–3272. 2014. View Article : Google Scholar : PubMed/NCBI
15	Soderlund K, Skoog L, Fornander T and Askmalm MS: The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer. Radiother Oncol. 84:242–251. 2007. View Article : Google Scholar : PubMed/NCBI
16	Sosinska-Mielcarek K, Duchnowska R, Winczura P, Badzio A, Majewska H, Lakomy J, Pęksa R, Pieczyńska B, Radecka B, Dębska S, et al: Immunohistochemical prediction of brain metastases in patients with advanced breast cancer: The role of Rad51. Breast. 22:1178–1183. 2013. View Article : Google Scholar : PubMed/NCBI
17	Alshareeda AT, Negm OH, Aleskandarany MA, Green AR, Nolan C, TigHhe PJ, Madhusudan S, Ellis IO and Rakha EA: Clinical and biological significance of RAD51 expression in breast cancer: A key DNA damage response protein. Breast Cancer Res Treat. 159:41–53. 2016. View Article : Google Scholar : PubMed/NCBI
18	Chiu WC, Fang PT, Lee YC, Wang YY, Su YH, Hu SC, Chen YK, Tsui YT, Kao YH, Huang MY and Yuan SF: DNA Repair Protein Rad51 induces tumor growth and metastasis in esophageal squamous cell carcinoma via a p38/Akt-Dependent pathway. Ann Surg Oncol. 27:2090–2101. 2020. View Article : Google Scholar
19	Yuan SS, Hou MF, Hsieh YC, Huang CY, Lee YC, Chen YJ and Lo S: Role of MRE11 in cell proliferation, tumor invasion, and DNA repair in breast cancer. J Natl Cancer Inst. 104:1485–1502. 2012. View Article : Google Scholar : PubMed/NCBI
20	Liu Y, Lu LL, Wen D, Liu DL, Dong LL, Gao DM, Bian XY, Zhou J, Fan J and Wu WZ: MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming. J Hematol Oncol. 13:122020. View Article : Google Scholar : PubMed/NCBI
21	Lee MY, Huang CH, Kuo CJ, Lin CL, Lai WT and Chiou SH: Clinical proteomics identifies urinary CD14 as a potential biomarker for diagnosis of stable coronary artery disease. PLoS One. 10:e01171692015. View Article : Google Scholar : PubMed/NCBI
22	Cottrell JS: Protein identification using MS/MS data. J Proteomics. 74:1842–1851. 2011. View Article : Google Scholar : PubMed/NCBI
23	Nedeljkovic M and Damjanovic A: Mechanisms of chemotherapy resistance in triple-negative breast cancer-how we can rise to the challenge. Cells. 8:9572019. View Article : Google Scholar : PubMed/NCBI
24	Prihantono and Faruk M: Breast cancer resistance to chemotherapy: When should we suspect it and how can we prevent it? Ann Med Surg. 70:1027932021. View Article : Google Scholar
25	Holliday DL and Speirs V: Choosing the right cell line for breast cancer research. Breast Cancer Res. 13:2152011. View Article : Google Scholar : PubMed/NCBI
26	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
27	Guney Eskiler G, Sahin E, Deveci Ozkan A, Cilingir Kaya OT and Kaleli S: Curcumin induces DNA damage by mediating homologous recombination mechanism in triple negative breast cancer. Nutr Cancer. 72:1057–1066. 2020. View Article : Google Scholar
28	Gildemeister OS, Sage JM and Knight KL: Cellular redistribution of Rad51 in response to DNA damage: Novel role for Rad51C. J Biol Chem. 284:31945–31952. 2009. View Article : Google Scholar : PubMed/NCBI
29	Mladenov E, Anachkova B and Tsaneva I: Sub-nuclear localization of Rad51 in response to DNA damage. Genes Cells. 11:513–524. 2006. View Article : Google Scholar : PubMed/NCBI
30	Dugina VB, Shagieva GS and Kopnin PB: Biological role of actin isoforms in mammalian cells. Biochemistry. 84:583–592. 2019.PubMed/NCBI
31	Bunnell TM, Burbach BJ, Shimizu Y and Ervasti JM: β-Actin specifically controls cell growth, migration, and the G-actin pool. Mol Biol Cell. 22:4047–4058. 2011. View Article : Google Scholar : PubMed/NCBI
32	Suresh R and Diaz RJ: The remodelling of actin composition as a hallmark of cancer. Transl Oncol. 14:1010512021. View Article : Google Scholar : PubMed/NCBI
33	Gourley C, Balmana J, Ledermann JA, Serra V, Dent R, Loibl S, Pujade-Lauraine E and Boulton SJ: Moving from poly (ADP-ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy. J Clin Oncol. 37:2257–2269. 2019. View Article : Google Scholar : PubMed/NCBI
34	Honrado E, Osorio A, Palacios J, Milne RL, Sánchez L, Díez O, Cazorla A, Syrjakoski K, Huntsman D, Heikkilä P, et al: Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors. J Clin Oncol. 23:7503–7511. 2005. View Article : Google Scholar : PubMed/NCBI
35	Klein HL: The consequences of Rad51 overexpression for normal and tumor cells. DNA Repair. 7:686–693. 2008. View Article : Google Scholar : PubMed/NCBI
36	Gachechiladze M, Skarda J, Soltermann A and Joerger M: RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies. Int J Cancer. 141:1286–1294. 2017. View Article : Google Scholar : PubMed/NCBI
37	Stodtmann S, Nuthalapati S, Eckert D, Kasichayanula S, Joshi R, Bach BA, Mensing S, Menon R and Xiong H: A population pharmacokinetic meta-analysis of veliparib, a PARP inhibitor, across phase 1/2/3 trials in cancer patients. J Clin Pharmacol. 61:1195–1205. 2021. View Article : Google Scholar : PubMed/NCBI
38	Wiegmans AP, Yap PY, Ward A, Lim YC and Khanna KK: Differences in expression of key DNA damage repair genes after epigenetic-Induced BRCAness dictate synthetic lethality with PARP1 inhibition. Mol Cancer Ther. 14:2321–2331. 2015. View Article : Google Scholar : PubMed/NCBI
39	Yoneda T, Williams PJ, Hiraga T, Niewolna M and Nishimura R: A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J Bone Miner Res. 16:1486–1495. 2001. View Article : Google Scholar : PubMed/NCBI
40	Woditschka S, Evans L, Duchnowska R, Reed LT, Palmieri D, Qian Y, Badve S, Sledge G Jr, Gril B, Aladjem MI, et al: DNA double-strand break repair genes and oxidative damage in brain metastasis of breast cancer. J Natl Cancer Inst. 106:dju1452014. View Article : Google Scholar : PubMed/NCBI
41	Wang J and Xu B: Targeted therapeutic options and future perspectives for HER2-positive breast cancer. Signal Transduct Target Ther. 4:342019. View Article : Google Scholar : PubMed/NCBI
42	Nam S, Chang HR, Jung HR, Gim Y, Kim NY, Grailhe R, Seo HR, Park HS, Balch C, Lee J, et al: A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer. Cancer Lett. 356:880–890. 2015. View Article : Google Scholar
43	Negrini S, Gorgoulis VG and Halazonetis TD: Genomic instability-an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 11:220–228. 2010. View Article : Google Scholar : PubMed/NCBI
44	Schild D and Wiese C: Overexpression of RAD51 suppresses recombination defects: A possible mechanism to reverse genomic instability. Nucleic Acids Res. 38:1061–1070. 2010. View Article : Google Scholar :
45	Chen CC, Feng W, Lim PX, Kass EM and Jasin M: Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in genome integrity and cancer. Annu Rev Cancer Biol. 2:313–336. 2018. View Article : Google Scholar : PubMed/NCBI
46	Scully R, Xie A and Nagaraju G: Molecular functions of BRCA1 in the DNA damage response. Cancer Biol Ther. 3:521–527. 2004. View Article : Google Scholar : PubMed/NCBI
47	Plo I, Laulier C, Gauthier L, Lebrun F, Calvo F and Lopez BS: AKT1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD51. Cancer Res. 68:9404–9412. 2008. View Article : Google Scholar : PubMed/NCBI
48	Yuan SS, Lee SY, Chen G, Song M, Tomlinson GE and Lee EY: BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res. 59:3547–3551. 1999.PubMed/NCBI
49	Davies AA, Masson JY, McIlwraith MJ, Stasiak AZ, Stasiak A, Venkitaraman AR and West SC: Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 7:273–282. 2001. View Article : Google Scholar : PubMed/NCBI
50	Suwaki N, Klare K and Tarsounas M: RAD51 paralogs: Roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Dev Biol. 22:898–905. 2011. View Article : Google Scholar : PubMed/NCBI
51	Jeyasekharan AD, Liu Y, Hattori H, Pisupati V, Jonsdottir AB, Rajendra E, Lee M, Sundaramoorthy E, Schlachter S, Kaminski CF, et al: A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 20:1191–1198. 2013. View Article : Google Scholar : PubMed/NCBI
52	Paul A and Paul S: The breast cancer susceptibility genes (BRCA) in breast and ovarian cancers. Front Biosci. 19:605–618. 2014. View Article : Google Scholar
53	Zhao W, Wiese C, Kwon Y, Hromas R and Sung P: The BRCA tumor suppressor network in chromosome damage repair by homologous recombination. Annu Rev Biochem. 88:221–245. 2019. View Article : Google Scholar : PubMed/NCBI
54	Paterson EK and Courtneidge SA: Invadosomes are coming: New insights into function and disease relevance. FEBS J. 285:8–27. 2018. View Article : Google Scholar :
55	Izdebska M, Zielinska W, Grzanka D and Gagat M: The role of actin dynamics and actin-binding proteins expression in epithelial-to-mesenchymal transition and its association with cancer progression and evaluation of possible therapeutic targets. Biomed Res Int. 2018:45783732018. View Article : Google Scholar : PubMed/NCBI
56	Nersesian S, Williams R, Newsted D, Shah K, Young S, Evans PA, Allingham JS and Craig AW: Effects of modulating actin dynamics on HER2 cancer cell motility and metastasis. Sci Rep. 8:172432018. View Article : Google Scholar : PubMed/NCBI
57	van Wijk LM, Nilas AB, Vrieling H and Vreeswijk MPG: RAD51 as a functional biomarker for homologous recombination deficiency in cancer: A promising addition to the HRD toolbox? Expert Rev Mol Diagn. 22:185–199. 2022. View Article : Google Scholar