Expressions of ALDH1 and SOX2 protein in breast cancer tissues and their clinical significance_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

PAN Xinyue ^1,2 ,  ZHANG Hao ² , WANG Zheng ²

1. Graduate School, Xinxiang Medical College, Xinxiang, Henan 453000, P. R. China;
2. Department of Breast Surgery, Nanyang Central Hospital, Nanyang, Henan 473000, P. R. China;

Corresponding author：

ZHANG Hao, Email: ewk0377@126.com

Keywords：

breast cancer; aldehyde dehydrogenase 1; sex determining region Y-box protein 2; immunohistochemistry; prognosis

DOI：

10.7507/1007-9424.202303044

Video：

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Objective To investigate the expressions of aldehyde dehydrogenase 1 (ALDH1) and sex determining region Y-box protein 2 (SOX2) in breast cancer tissues and their clinical significance. Methods Immunohistochemistry was used to detect the expressions of ALDH1 and SOX2 protein in cancerous and its paracancer tissues of 80 patients with breast cancer treated in our hospital from 2017 to 2019, and to analyze the correlation between the expressions of ALDH1 and SOX2 protein, as well as the relationship between their expression and clinicopathological characteristics and prognosis of breast cancer patients. Results The positive expression rates of ALDH1 and SOX2 protein in breast cancer tissues were 75.0% and 62.5%, respectively. The positive expression rates of ALDH1 and SOX2 protein in paracancer tissues were 30.0% and 21.3%, respectively. The positive rates of ALDH1 and SOX2 protein expressions in breast cancer tissues were higher than those in paracancer tissues, and the difference was statistically significant (P<0.05). The expressions of ALDH1 and SOX2 proteins in breast cancer tissues were correlated with histological grade, TNM stage and axillary lymph node status of breast cancer (P<0.05). By Spearman correlation analysis, ALDH1 was positively correlated with SOX2 expression (r_s=0.507, P<0.001). The univariate analysis of statistically significant indicators and the combination of clinical characteristics of the logistic regression multivariate analysis found that, breast cancer tumor size, histological grade, TNM stage, axillary lymph node status and ALDH1 protein and SOX2 protein expressions were not significantly correlated with those reaching disease-free survival (DFS) after follow-up (P>0.05, which may be affected by small sample size and small number of endpoint events). The Kaplan-Meier method was used to plot survival curves, and log-rank test results showed that the cumulative DFS rates of patients with positive ALDH1 and SOX2 protein expression were lower than those of with negative expression (P<0.05). Conclusions ALDH1 and SOX2 proteins are highly expressed in breast cancer tissues, and they are positively correlated. Survival curves show that positive ALDH1 and SOX2 proteins in breast cancer tissues tend to have a poorer prognosis.

Citation： PAN Xinyue, ZHANG Hao, WANG Zheng. Expressions of ALDH1 and SOX2 protein in breast cancer tissues and their clinical significance. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(7): 802-807. doi: 10.7507/1007-9424.202303044 Copy

1.	Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90.
2.	Lin F, Xie YJ, Zhang XK, et al. GTSE1 is involved in breast cancer progression in p53 mutation-dependent manner. J Exp Clin Cancer Res, 2019, 38(1): 152. doi: 10.1186/s13046-019-1157-4.
3.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
4.	Wu TF, Li YC, Ma SR, et al. Expression and associations of TRAF1, BMI-1, ALDH1, and Lin28B in oral squamous cell carcinoma. Tumour Biol, 2017, 39(4): 1010428317695930. doi: 10.1177/1010428317695930.
5.	柴烁, 张强, 李玉云. ALDH1作为干细胞标志物在胃癌中的研究进展. 医学理论与实践, 2019, 32(6): 814-816.
6.	Malinee M, Kumar A, Hidaka T, et al. Targeted suppression of metastasis regulatory transcription factor SOX2 in various cancer cell lines using a sequence-specific designer pyrrole-imidazole polyamide. Bioorg Med Chem, 2020, 28(3): 115248. doi: 10.1016/j.bmc.2019.115248.
7.	Marchitti SA, Brocker C, Stagos D, et al. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol, 2008, 4(6): 697-720.
8.	姚晋林, 姚孟飞, 窦坤, 等. SOX2和OCT4基因蛋白在乳腺癌中的表达及临床意义的研究. 中国药物与临床, 2015, 15(5): 610-613.
9.	Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
10.	Graham D, DiNome ML, Ganz PA. Breast cancer risk-reducing medications. JAMA, 2020, 324(3): 310. doi: 10.1001/jama.2020.11784.
11.	袁会军, 刘斌, 于文庆, 等. Chk1在乳腺癌组织中的表达及临床病理意义. 现代肿瘤医学, 2022, 30(3): 456-459.
12.	Bao C, Chen J, Chen D, et al. MiR-93 suppresses tumorigenesis and en-hances chemosensitivity of breast cancer via dual targeting E2F1 and CCND1. Cell Death Dis, 2020, 11(8): 618. doi: 10.1038/s41419-020-02855-6.
13.	MacDonagh L, Santiago RM, Gray SG, et al. Exploitation of the vita-jmin A/retinoic acid axis depletes ALDH1-positive cancer stem cells jand re-sensitises resistant non-small cell lung cancer cells to cisplatin. Transl Oncol, 2021, 14(4): 101025. doi: 10.1016/.tranon.2021.101025.
14.	Kiefer FW, Orasanu G, Nallamshetty S, et al. Retinaldehyde dehydrogenase 1 coordinates hepatic gluconeogenesis and lipid metabolism. Endocrinology, 2012, 153(7): 3089-3099.
15.	Cañestro C, Catchen JM, Rodríguez-Marí A, et al. Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes. PLoS Genet, 2009, 5(5): e1000496. doi: 10.1371/journal.pgen.1000496.
16.	焦园园, 张金金, 李万颖, 等. 乙醛脱氢酶1在宫颈癌发生发展中作用的研究进展. 吉林大学学报(医学版), 2017, 43(1): 196-199.
17.	Yao T, Chen Q, Zhang B, et al. The expression of ALDH1 in cervical carcinoma. Med Sci Monit, 2011, 17(8): HY21-HY26.
18.	Wakamatsu Y, Sakamoto N, Oo HZ, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int, 2012, 62(2): 112-119.
19.	刘翠翠, 张立行, 柳素玲. 肿瘤干细胞标志物ALDH1A1通过重塑免疫微环境促进乳腺癌进展. 中国细胞生物学学报, 2022, 44(3): 405-412.
20.	徐晶晶, 邱岑, 郑建明. 乳腺癌组织中ALDH1、BRCA1、nm23蛋白表达变化及意义. 山东医药, 2020, 60(28): 50-53.
21.	Stevanovic M, Zuffardi O, Collignon J, et al. The cDNA sequence and chromosomal location of the human SOX2 gene. Mamm Genome, 1994, 5(10): 640-642.
22.	Novak D, Hüser L, Elton JJ, et al. SOX2 in development and cancer biology. Semin Cancer Biol, 2020, 67(Pt 1): 74-82.
23.	Weina K, Utikal J. SOX2 and cancer: current research and its implications in the clinic. Clin Transl Med, 2014, 3: 19. doi: 10.1186/2001-1326-3-19.
24.	Hüser L, Novak D, Umansky V, et al. Targeting SOX2 in anticancer therapy. Expert Opin Ther Targets, 2018, 22(12): 983-991.
25.	Wang J, Zeng H, Li H, et al. MicroRNA-101 inhibits growth, proliferation and migration and induces apoptosis of breast cancer cells by targeting sex-determining region Y-box 2. Cell Physiol Biochem, 2017, 43(2): 717-732.
26.	Yang F, Zhang J, Yang H. 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, 2018, 11: 7873-7881.
27.	Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 2007, 1(5): 555-567.
28.	Sarkar A, Hochedlinger K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell, 2013, 12(1): 15-30.
29.	Wang XY, Penalva LO, Yuan H, et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol Cancer, 2010, 9: 221. doi: 10.1186/1476-4598-9-221.
30.	Liu K, Xie F, Gao A, et al. SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis. Mol Cancer, 2017, 16(1): 62. doi: 10.1186/s12943-017-0632-9.
31.	Wu F, Ye X, Wang P, et al. Sox2 suppresses the invasiveness of breast cancer cells via a mechanism that is dependent on Twist1 and the status of Sox2 transcription activity. BMC Cancer, 2013, 13: 317. doi: 10.1186/1471-2407-13-317.
32.	Wang Y, Zhou J, Wang Z, et al. Upregulation of SOX2 activated LncRNA PVT1 expression promotes breast cancer cell growth and invasion. Biochem Biophys Res Commun, 2017, 493(1): 429-436.

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90.
2. Lin F, Xie YJ, Zhang XK, et al. GTSE1 is involved in breast cancer progression in p53 mutation-dependent manner. J Exp Clin Cancer Res, 2019, 38(1): 152. doi: 10.1186/s13046-019-1157-4.
3. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
4. Wu TF, Li YC, Ma SR, et al. Expression and associations of TRAF1, BMI-1, ALDH1, and Lin28B in oral squamous cell carcinoma. Tumour Biol, 2017, 39(4): 1010428317695930. doi: 10.1177/1010428317695930.
5. 柴烁, 张强, 李玉云. ALDH1作为干细胞标志物在胃癌中的研究进展. 医学理论与实践, 2019, 32(6): 814-816.
6. Malinee M, Kumar A, Hidaka T, et al. Targeted suppression of metastasis regulatory transcription factor SOX2 in various cancer cell lines using a sequence-specific designer pyrrole-imidazole polyamide. Bioorg Med Chem, 2020, 28(3): 115248. doi: 10.1016/j.bmc.2019.115248.
7. Marchitti SA, Brocker C, Stagos D, et al. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol, 2008, 4(6): 697-720.
8. 姚晋林, 姚孟飞, 窦坤, 等. SOX2和OCT4基因蛋白在乳腺癌中的表达及临床意义的研究. 中国药物与临床, 2015, 15(5): 610-613.
9. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl), 2022, 135(5): 584-590.
10. Graham D, DiNome ML, Ganz PA. Breast cancer risk-reducing medications. JAMA, 2020, 324(3): 310. doi: 10.1001/jama.2020.11784.
11. 袁会军, 刘斌, 于文庆, 等. Chk1在乳腺癌组织中的表达及临床病理意义. 现代肿瘤医学, 2022, 30(3): 456-459.
12. Bao C, Chen J, Chen D, et al. MiR-93 suppresses tumorigenesis and en-hances chemosensitivity of breast cancer via dual targeting E2F1 and CCND1. Cell Death Dis, 2020, 11(8): 618. doi: 10.1038/s41419-020-02855-6.
13. MacDonagh L, Santiago RM, Gray SG, et al. Exploitation of the vita-jmin A/retinoic acid axis depletes ALDH1-positive cancer stem cells jand re-sensitises resistant non-small cell lung cancer cells to cisplatin. Transl Oncol, 2021, 14(4): 101025. doi: 10.1016/.tranon.2021.101025.
14. Kiefer FW, Orasanu G, Nallamshetty S, et al. Retinaldehyde dehydrogenase 1 coordinates hepatic gluconeogenesis and lipid metabolism. Endocrinology, 2012, 153(7): 3089-3099.
15. Cañestro C, Catchen JM, Rodríguez-Marí A, et al. Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes. PLoS Genet, 2009, 5(5): e1000496. doi: 10.1371/journal.pgen.1000496.
16. 焦园园, 张金金, 李万颖, 等. 乙醛脱氢酶1在宫颈癌发生发展中作用的研究进展. 吉林大学学报(医学版), 2017, 43(1): 196-199.
17. Yao T, Chen Q, Zhang B, et al. The expression of ALDH1 in cervical carcinoma. Med Sci Monit, 2011, 17(8): HY21-HY26.
18. Wakamatsu Y, Sakamoto N, Oo HZ, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int, 2012, 62(2): 112-119.
19. 刘翠翠, 张立行, 柳素玲. 肿瘤干细胞标志物ALDH1A1通过重塑免疫微环境促进乳腺癌进展. 中国细胞生物学学报, 2022, 44(3): 405-412.
20. 徐晶晶, 邱岑, 郑建明. 乳腺癌组织中ALDH1、BRCA1、nm23蛋白表达变化及意义. 山东医药, 2020, 60(28): 50-53.
21. Stevanovic M, Zuffardi O, Collignon J, et al. The cDNA sequence and chromosomal location of the human SOX2 gene. Mamm Genome, 1994, 5(10): 640-642.
22. Novak D, Hüser L, Elton JJ, et al. SOX2 in development and cancer biology. Semin Cancer Biol, 2020, 67(Pt 1): 74-82.
23. Weina K, Utikal J. SOX2 and cancer: current research and its implications in the clinic. Clin Transl Med, 2014, 3: 19. doi: 10.1186/2001-1326-3-19.
24. Hüser L, Novak D, Umansky V, et al. Targeting SOX2 in anticancer therapy. Expert Opin Ther Targets, 2018, 22(12): 983-991.
25. Wang J, Zeng H, Li H, et al. MicroRNA-101 inhibits growth, proliferation and migration and induces apoptosis of breast cancer cells by targeting sex-determining region Y-box 2. Cell Physiol Biochem, 2017, 43(2): 717-732.
26. Yang F, Zhang J, Yang H. 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, 2018, 11: 7873-7881.
27. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 2007, 1(5): 555-567.
28. Sarkar A, Hochedlinger K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell, 2013, 12(1): 15-30.
29. Wang XY, Penalva LO, Yuan H, et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol Cancer, 2010, 9: 221. doi: 10.1186/1476-4598-9-221.
30. Liu K, Xie F, Gao A, et al. SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis. Mol Cancer, 2017, 16(1): 62. doi: 10.1186/s12943-017-0632-9.
31. Wu F, Ye X, Wang P, et al. Sox2 suppresses the invasiveness of breast cancer cells via a mechanism that is dependent on Twist1 and the status of Sox2 transcription activity. BMC Cancer, 2013, 13: 317. doi: 10.1186/1471-2407-13-317.
32. Wang Y, Zhou J, Wang Z, et al. Upregulation of SOX2 activated LncRNA PVT1 expression promotes breast cancer cell growth and invasion. Biochem Biophys Res Commun, 2017, 493(1): 429-436.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expressions of ALDH1 and SOX2 protein in breast cancer tissues and their clinical significance

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