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中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2020, Vol. 14 ›› Issue (01) : 37 -43. doi: 10.3877/cma.j.issn.1674-0807.2020.01.010

所属专题： 文献；

论著

金属硫样蛋白5在乳腺癌组织中的表达及其与预后的关系
肖冰兰1, 丁波泥1, 吴唯1, 文言广1, 钱立元1,†()   
  1. 1. 410013　长沙，中南大学湘雅三医院乳甲外科
  • 收稿日期:2019-04-08 出版日期:2020-02-01
  • 通信作者: 钱立元
  • 基金资助:
    长沙市科技计划基础研究项目(kq1801117)

Metallothionein-like 5 expression in breast cancer tissue and its relationship with patient prognosis

Binglan Xiao1, Boni Ding1, Wei Wu1, Yanguang Wen1, Liyuan Qian1,†()   

  1. 1. Department of Breast and Thyroid Surgery, Third Xiangya Hospital of Central South University, Changsha 410013, China
  • Received:2019-04-08 Published:2020-02-01
  • Corresponding author: Liyuan Qian
  • About author:
    Corresponding author: Qian Liyuan, Email:
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引用本文：

肖冰兰, 丁波泥, 吴唯, 文言广, 钱立元. 金属硫样蛋白5在乳腺癌组织中的表达及其与预后的关系[J/OL]. 中华乳腺病杂志(电子版), 2020, 14(01): 37-43.

Binglan Xiao, Boni Ding, Wei Wu, Yanguang Wen, Liyuan Qian. Metallothionein-like 5 expression in breast cancer tissue and its relationship with patient prognosis[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2020, 14(01): 37-43.

目的

探讨金属硫样蛋白5(MTL5)在乳腺癌组织中的表达与患者预后的关系。

方法

本回顾性研究采用在中国人类遗传资源共享服务平台(编号：2005DKA2130)获得的2005年1月至2012年9月初次手术、术前无肿瘤远处转、未经过新辅助治疗的77例乳腺癌患者的癌组织和癌旁组织标本进行免疫组织化学实验。术后随访截止至2016年1月，随访时间为3.3～11.0年。用χ2检验、Fisher精确概率法及非参数检验分析MTL5在乳腺癌组织中表达与临床病理特征的关系；用Cox比例风险回归模型分析MTL5表达对患者复发和死亡风险的影响；用Kaplan-Meier法进行生存分析并绘制生存曲线；采用log-rank检验比较不同MTL5表达患者的OS率和无复发生存率。

结果

在纳入的77例成对样本中，排除脱片样本5例、癌组织和癌旁组织均无MTL5表达的样本29例、MTL5均有表达但差别无法判断的样本2例后，剩余41例，其中MTL5高表达(癌组织中MTL5表达高于癌旁组织)者21例，低表达(癌组织中MTL5表达低于癌旁组织)者20例。MTL5表达与年龄、腋窝淋巴结转移相关(P＝0.021；Z＝－2.281，P＝0.023)，而与ER、PR、肿瘤大小、病理类型、HER-2无关(χ2＝0.034，P＝0.853；χ2＝0.042，P＝0.837；χ2＝1.177，P＝0.278；P＝0.663；P＝1.000)。单因素分析显示：腋窝淋巴结转移及MTL5表达为复发和死亡风险因素(复发风险：N3期与N0期比较，HR＝14.524，90%CI: 2.322～90.858，P＝0.004；MTL5高表达者比低表达者，HR＝8.752, 90%CI: 1.093～70.054，P＝0.041；死亡风险：N3期与N0期比较，HR＝8.469，90%CI: 1.495～47.988，P＝0.016；MTL5高表达者比低表达者，HR＝8.255, 90%CI: 1.031～66.081，P＝0.047)。多因素分析显示：高表达MTL5的乳腺癌患者复发风险更高，且可以作为独立风险因素(HR＝11.320, 95%CI：1.022～125.436，P＝0.048)；同样，高表达MTL5的乳腺癌患者有更高的死亡风险，且可以作为独立风险因素(HR＝9.191, 95%CI：1.037～81.430，P＝0.046)。MTL5高表达者OS率及无复发生存率均低于MTL5低表达者(χ2＝5.652、6.084，P＝0.017、0.014)。

结论

MTL5在乳腺癌组织中高表达可提示患者预后差，有潜力作为乳腺癌的治疗靶点。

关键词: 乳腺肿瘤, 生存分析, 金属硫样蛋白5
Objective

To investigate the relationship of metallothionein-like 5(MTL5) expression in breast cancer tissue with the prognosis of breast cancer patients.

Methods

In our retrospective study, immunohistochemistry was performed on breast cancer tissue and corresponding paracancerous tissue samples of 77 patients who had no distant metastasis and neoadjuvant treatment before surgery and underwent the first surgery from January 2005 to September 2012, from the Chinese Human Genetic Resources Sharing Service Platform (No. 2005DKA2130). The patients were followed up for 3.3-11.0 years, until January 2016. Fisher’s exact test, χ2 test and non-parametric test were used to analyze the relationship between MTL5 expression in breast cancer tissues and clinicopathological characteristics of patients. Cox proportional hazard regression model was used to study the effect of MTL5 expression on recurrence and death risk of breast cancer patients.Kaplan-Meier method was used for survival analysis and the survival curves were plotted; log-rank test was used to compare the OS and recurrence-free survival between patients with high and low MTL5 expression.

Results

In the included 77 paired samples, 5 cases had detachment of the tissue sections from the slides, 29 cases had no MTL5 expression in cancer tissues and paracancerous tissues, and 2 cases had indiscernible difference in MTL5 expressions. So the aforementioned cases were excluded. In the remaining 41 cases, MTL5 expression in breast cancer tissues was significantly higher than that in paracancerous tissues in 21 cases, but lower in other 20 cases. MTL5 expression was correlated with age, axillary lymph node metastasis (P=0.021; Z=-2.281, P=0.023), but not correlated with ER, PR, tumor size, pathological type and HER-2 (χ2=0.034, P=0.853; χ2=0.042, P=0.837; χ2=1.177, P=0.278; P=0.663; P=1.000). Univariate analysis of the Cox proportional hazard regression model showed that axillary lymph node metastasis and MTL5 expression were risk factors for recurrence and death (recurrence: N3 stage vs N0 stage, HR=14.524, 90%CI: 2.322-90.858, P=0.004; high MTL5 expression vs low MTL5 expression, HR=8.752, 90%CI: 1.093-70.054, P=0.041; death: N3 stage vs N0 stage, HR=8.469, 90%CI: 1.495-47.988, P=0.016; high MTL5 expression vs low MTL5 expression, HR=8.255, 90%CI: 1.031-66.081, P=0.047). Multivariate analysis showed that breast cancer patients with high MTL5 expression had higher risk of recurrence compared with the patients with low MTL5 expression and MTL5 expression can be used as an independent risk factor of recurrence(HR=11.320, 95%CI: 1.022-125.436, P=0.048). Similarly, the patients with high MTL5 expression had higher risk of death compared with the patients with low MTL5 expression, so MTL5 expression can be used as an independent risk factor of death (HR=9.191, 95%CI: 1.037-81.430, P=0.046). The patients with high MTL5 expression had lower OS and recurrence-free survival compared with those with low MTL5 expression (χ2=5.652, 6.084; P=0.017, 0.014).

Conclusion

High MTL5 expression in breast cancer tissues may indicate a poor prognosis, so MTL5 can be used as a therapeutic target for breast cancer.

Key words: Breast neoplasms, Survival analysis, Metallothionein-like 5
图1 金属硫样蛋白5高表达的乳腺癌组织与对应癌旁组织的免疫组织化学图及病理图　a、b　图分别为癌组织的免疫组织化学图(SP ×400)　及病理图(HE ×400)；c、d　图分别为对应癌旁组织的免疫组织化学图(SP ×400)　及病理图(HE ×400)
图2 金属硫样蛋白5低表达的乳腺癌组织与对应癌旁组织的免疫组织化学图及病理图　a、b　图分别为癌组织的免疫组织化学图(SP ×400)　及病理图(HE ×400)；c、d　图分别为对应癌旁组织的免疫组织化学图(SP ×400)　及病理图(HE ×400)
表1 乳腺癌患者复发与死亡风险的Cox比例风险回归模型变量赋值表
因素 变量 变量赋值
年龄 X1 ≤65岁＝0，>65岁＝1
病理类型 X2 浸润性导管癌＝0，其他＝1
ER X3 阴性＝0，阳性＝1
PR X4 阴性＝0，阳性＝1
HER-2 X5 阴性＝0，阳性＝1
肿瘤大小 X6 ≤2 cm＝0，>2～5 cm＝1
液窝淋巴结转移 X7 N0＝0，N1＝1，N2＝2，N3＝3
MTL5表达 X8 癌组织中的表达低于癌旁组织＝0，癌组织中的表达高于癌旁组织＝1
无复发生存 Y1 无复发＝0,复发＝1
总生存 Y2 生存＝0,死亡＝1
表2 乳腺癌患者临床病理特征与MTL5表达的关系
临床病理特征 MTL5[例(%)] 检验值 P值
高表达(n＝21) 低表达(n＝20)
年龄 ? ? ? ?
? ≤65岁 15(71.4) 20(100) ? 0.021a
? > 65岁 6(26.6) 0(0)
病理类型 ? ? ? ?
? 浸润性导管癌 17(81.0) 18(90.0) ? 0.663a
? 其他 4(19.0) 2(10.0)
ER ? ? ? ?
? 阴性 9(42.9) 8(40.0) χ2＝0.034 0.853
? 阳性 12(57.1) 12(60.0)
PR ? ? ? ?
? 阴性 13(61.9) 13(65.0) χ2＝0.042 0.837
? 阳性 8(38.1) 7(35.0)
HER-2 ? ? ? ?
? 阴性 16(76.2) 16(80.0) ? 1.000a
? 阳性 5(23.8) 4(20.0)
肿瘤大小 ? ? ? ?
? ≤2 cm 8(38.1) 11(55.0) χ2＝1.177 0.278
? >2～5 cm 13(61.9) 9(45.0)
腋窝淋巴结转移 ? ? ? ?
? N0 10(47.6) 16(80.0) ? 0.023b
? N1 1(4.8) 1(5.0)
? N2 8(38.1) 3(15.0)
? N3 2(9.5) 0(0)
表3 乳腺癌患者复发风险的Cox比例风险回归模型单因素分析(n＝41)
临床病理特征 HR 95%CI P值
年龄 ? ? ?
? ≤65岁 1.000 ? ?
? >65岁 2.245 0.465～10.834 0.314
病理类型 ? ? ?
? 浸润性导管癌 1.000 ? ?
? 其他 1.685 0.350～8.120 0.515
ER ? ? ?
? 阴性 1.000 ? ?
? 阳性 0.325 0.081～1.301 0.099
PR ? ? ?
? 阴性 1.000 ? ?
? 阳性 0.538 0.112～2.589 0.439
HER-2 ? ? ?
? 阴性 1.000 ? ?
? 阳性 1.022 0.212～4.924 0.978
肿瘤大小 ? ? ?
? ≤2 cm 1.000 ? ?
? >2～5 cm 1.830 0.487～6.803 0.373
腋窝淋巴结转移 ? ? ?
? N0 1.000 ? 0.041
? N1 0.989 0 0.989
? N2 1.843 0.412～8.237 0.423
? N3 14.524 2.322～90.858 0.004
MTL5 ? ? ?
? 低表达 1.000 ? ?
? 高表达 8.752 1.093～70.054 0.041
表4 乳腺癌患者复发风险的Cox比例风险回归模型多因素分析(n＝41)
临床病理特征 HR 95%CI P值
腋窝淋巴结转移 ? ? ?
? N0 1.000 ? 0.278
? N1 0 0 0.991
? N2 0.906 0.175～4.677 0.906
? N3 6.241 0.751～51.832 0.091
金属硫样蛋白5 ? ? ?
? 低表达 1.000 ? ?
? 高表达 11.320 1.022～125.436 0.048
表5 乳腺癌患者死亡风险的Cox比例风险回归模型单因素分析(n＝41)
临床病理特征 HR 95%CI P值
病理类型 ? ? ?
浸润性导管癌 1.000 ? ?
? 其他 1.703 0.353～8.220 0.507
ER ? ? ?
? 阴性 1.000 ? ?
? 阳性 0.347 0.087～1.387 0.134
PR ? ? ?
? 阴性 1.000 ? ?
? 阳性 1.007 0.251～4.035 0.992
HER-2 ? ? ?
? 阴性 1.000 ? ?
? 阳性 1.022 0.202～4.674 0.970
肿瘤大小 ? ? ?
? ≤2 cm 1.000 ? ?
? >2～5 cm 2.694 0.672～10.789 0.162
腋窝淋巴结转移 ? ? ?
? N0 1.000 ? 0.130
? N1 0 0 0.998
? N2 1.812 0.405～8.100 0.437
? N3 8.469 1.495～47.988 0.016
MTL5 ? ? ?
? 低表达 1.000 ? ?
? 高表达 8.255 1.031～66.081 0.047
表6 乳腺癌患者死亡风险的Cox比例风险回归模型多因素分析(n＝41)
临床病理特征 HR 95%CI P值
腋窝淋巴结转移 ? ? ?
? N0 1.000 ? 0.772
? N1 0 0 0.991
? N2 1.029 0.220～4.800 0.971
? N3 2.508 0.396～15.894 0.329
金属硫样蛋白5 ? ? ?
? 低表达 1.000 ? ?
? 高表达 9.191 1.037～81.430 0.046
图3 41例乳腺癌患者的总生存曲线
图4 41例乳腺癌患者的无复发生存曲线
[1]
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin, 2015, 65(2): 87-108.
[2]
Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Akinyemiju TF, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study[J]. JAMA Oncol, 2018, 4(11): 1553-1568.
[3]
Denkert C, Liedtke C, Tutt A, et al. Molecular alterations in triple-negative breast cancer-the road to new treatment strategies[J]. Lancet, 2017, 389(10087): 2430-2442.
[4]
Sutou S, Miwa K, Matsuura T, et al. Native tesmin is a 60-kilodalton protein that undergoes dynamic changes in its localization during spermatogenesis in mice[J]. Biol Reprod, 2003, 68(5): 1861-1869.
[5]
Brown GR, Hem V, Katz KS, et al. Gene: a gene-centered information resource at NCBI[J]. Nucleic Acids Res, 2015, 43(Database issue): D36-42.
[6]
The human protein atlas. Bethesda(MD)：National Cancer Institute[DB/OL]. [2019-04-01]．

URL    
[7]
Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses[J]. Neoplasia, 2017，19(8)：649-658.
[8]
Giuliano AE, Edge SB, Hortobagyi GN. Eighth edition of the AJCC cancer staging manual: breast cancer [J]. Ann Surg Oncol, 2018, 25(7): 1783-1785.
[9]
Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue [J]. Pathologe, 1987, 8(3): 138-140.
[10]
Compton C, Fenoglio-Preiser CM, Pettigrew N, et al. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group[J]. Cancer, 2000, 88(7): 1739-1757.
[11]
Nielsen AE, Bohr A, Penkowa M. The balance between life and death of cells: roles of metallothioneins[J]. Biomark Insights, 2007, 1: 99-111.
[12]
Cherian MG, Jayasurya A, Bay BH. Metallothioneins in human tumors and potential roles in carcinogenesis[J]. Mutat Res, 2003, 533(1/2): 201-209.
[13]
Kim HG, Kim JY, Han EH, et al. Metallothionein-2A overexpression increases the expression of matrix metalloproteinase-9 and invasion of breast cancer cells[J]. FEBS Lett, 2011, 585(2): 421-428.
[14]
Ostrakhovitch EA, Olsson PE, Jiang S, et al. Interaction of metallothionein with tumor suppressor p53 protein[J]. FEBS Lett, 2006, 580(5): 1235-1238.
[15]
Ostrakhovitch EA, Olsson PE, Von Hofsten J, et al. P53 mediated regulation of metallothionein transcription in breast cancer cells[J]. J Cell Biochem, 2007, 102(6): 1571-1583.
[16]
Aure MR, Steinfeld I, Baumbusch LO, et al. Identifying in-trans process associated genes in breast cancer by integrated analysis of copy number and expression data[J]. PLoS One, 2013, 8(1): e53014.
[17]
Matsuura T, Kawasaki Y, Miwa K, et al. Germ cell-specific nucleocytoplasmic shuttling protein, tesmin, responsive to heavy metal stress in mouse testes[J]. J Inorg Biochem, 2002, 88(2): 183-191.
[18]
Nartey N, Cherian MG, Banerjee D. Immunohistochemical localization of metallothionein in human thyroid tumors[J]. Am J Pathol, 1987, 129(1): 177-182.
[19]
Nagel WW, Vallee BL. Cell cycle regulation of metallothionein in human colonic cancer cells[J]. Proc Natl Acad Sci U S A, 1995, 92(2): 579-583.
[20]
Liu Z, Running MP, Meyerowitz EM. TSO1 functions in cell division during Arabidopsis flower development[J]. Development, 1997, 124(3): 665-672.
[21]
Fuller PJ. Novel interactions of the mineralocorticoid receptor[J]. Mol Cell Endocrinol, 2015, 408: 33-37.
[22]
Mirshahi M, Golestaneh N, Valamanesh F, et al. Paradoxical effects of mineralocorticoids on the ion gated sodium channel in embryologically diverse cells[J]. Biochem Biophys Res Commun, 2000, 270(3): 811-815.
[23]
Archer NP, Perez-Andreu V, Scheurer ME, et al. Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics[J]. Cancer, 2016, 122(23): 3697-3704.
[24]
Penney KL, Sinnott JA, Tyekucheva S, et al. Association of prostate cancer risk variants with gene expression in normal and tumor tissue[J]. Cancer Epidemiol Biomarkers Prev, 2015, 24(1): 255-260.
[25]
Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma[J]. N Engl J Med, 1991, 324(1): 1-8.
[26]
Folkman J. Angiogenesis and breast cancer[J]. J Clin Oncol, 1994, 12(3): 441-443.
[27]
Bourc’his D, Bestor TH. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L[J]. Nature, 2004, 431(7004): 96-99.
[28]
Popp C, Dean W, Feng S, et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency[J]. Nature, 2010, 463(7284): 1101-1105.
[29]
Workman P. Signal transduction inhibitors as novel anticancer drugs: where are we？[J]. Ann Oncol, 1992, 3(7): 527-531.
[30]
Fry DW, Bridges AJ, Denny WA, et al. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor[J]. Proc Natl Acad Sci U S A, 1998, 95(20): 12 022-12 027.
[31]
Zhang L, Lau YK, Xia W, et al. Tyrosine kinase inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells in athymic mice and sensitizes these cells to the inhibitory effect of paclitaxel[J]. Clin Cancer Res, 1999, 5(2): 343-353.
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