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

doi:10.3877/cma.j.issn.1674-0807.2020.01.010

Abstract

Abstract:

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

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]. Chinese Journal of Breast Disease(Electronic Edition), 2020, 14(01): 37-43.

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References 31

[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.

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

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

临床病理特征		MTL5[例(%)]		检验值	P值
临床病理特征		高表达(n＝21)	低表达(n＝20)	检验值	P值
年龄		?	?	?	?
?	≤65岁	15(71.4)	20(100)	?	0.021^a
?	> 65岁	6(26.6)	0(0)	?	0.021^a
病理类型		?	?	?	?
?	浸润性导管癌	17(81.0)	18(90.0)	?	0.663^a
?	其他	4(19.0)	2(10.0)	?	0.663^a
ER		?	?	?	?
?	阴性	9(42.9)	8(40.0)	χ²＝0.034	0.853
?	阳性	12(57.1)	12(60.0)	χ²＝0.034	0.853
PR		?	?	?	?
?	阴性	13(61.9)	13(65.0)	χ²＝0.042	0.837
?	阳性	8(38.1)	7(35.0)	χ²＝0.042	0.837
HER-2		?	?	?	?
?	阴性	16(76.2)	16(80.0)	?	1.000^a
?	阳性	5(23.8)	4(20.0)	?	1.000^a
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)	χ²＝1.177	0.278
腋窝淋巴结转移		?	?	?	?
?	N₀	10(47.6)	16(80.0)	?	0.023^b
?	N₁	1(4.8)	1(5.0)
?	N₂	8(38.1)	3(15.0)
?	N₃	2(9.5)	0(0)

临床病理特征		MTL5[例(%)]		检验值	P值
临床病理特征		高表达(n＝21)	低表达(n＝20)	检验值	P值
年龄		?	?	?	?
?	≤65岁	15(71.4)	20(100)	?	0.021^a
?	> 65岁	6(26.6)	0(0)	?	0.021^a
病理类型		?	?	?	?
?	浸润性导管癌	17(81.0)	18(90.0)	?	0.663^a
?	其他	4(19.0)	2(10.0)	?	0.663^a
ER		?	?	?	?
?	阴性	9(42.9)	8(40.0)	χ²＝0.034	0.853
?	阳性	12(57.1)	12(60.0)	χ²＝0.034	0.853
PR		?	?	?	?
?	阴性	13(61.9)	13(65.0)	χ²＝0.042	0.837
?	阳性	8(38.1)	7(35.0)	χ²＝0.042	0.837
HER-2		?	?	?	?
?	阴性	16(76.2)	16(80.0)	?	1.000^a
?	阳性	5(23.8)	4(20.0)	?	1.000^a
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)	χ²＝1.177	0.278
腋窝淋巴结转移		?	?	?	?
?	N₀	10(47.6)	16(80.0)	?	0.023^b
?	N₁	1(4.8)	1(5.0)
?	N₂	8(38.1)	3(15.0)
?	N₃	2(9.5)	0(0)

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

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