复发转移乳腺癌中ERK、JNK/MAPK通路的激活或抑制及FAK、Ezrin、Paxillin、Integrinβ3、TrkC的表达与ERK/MAPK通路关系的研究
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摘要
研究目的:丝裂原活化蛋白激酶(MAPK)包括ERK、JNK等,它是细胞内重要的信号传导通路,在细胞的恶性转化和肿瘤的发生发展中起重要作用。FAK、Ezrin、Paxillin、Integrinβ3、TrkC可能与此信号传导通路有关。本研究检测ERK、JNK、FAK、Ezrin、Paxillin、Integrinβ3、TrkC在复发转移与未复发转移乳腺癌中的表达情况,探讨在复发转移乳腺癌中ERK、JNK/MAPK通路的激活情况,及FAK、Ezrin、Paxillin、Integrinβ3、TrkC的表达与ERK /MAPK通路的关系。
研究方法:收集1994-2006年广西医科大学第一附属医院外科及广西中医学院第一附属医院外科住院的女性乳腺癌患者共100例,收集临床资料,通过电话或通信随访,获得复发及生存情况。100例病人分成两个组:实验组为乳腺癌根治术后半年以上出现复发转移者共46例,标本取自1994-2006年在该两所医院手术并有完整的临床资料的患者,对照组为手术时间相近、发病年龄相近的乳腺癌根治术后未发生复发转移者共54例。石蜡封存组织块切片,应用免疫组织化学和核酸原位杂交技术,检测ERK、JNK、FAK、Integrinβ3、Paxillin、Ezrin、TrkC、ER、PR、CerbB-2在实验组、对照组的表达情况,并对实验组、对照组的临床病理因素进行研究。
研究结果:
1.ERK在实验组(复发转移组)与对照组(无复发转移组)中的阳性表达率分别为63.04%、38.89%,ERK在实验组中的表达较对照组显著增高(P<0.05);JNK在实验组与对照组中的阳性表达率分别为60.87%,75.93%(p>0.05),JNK在对照组中表达较与实验组高,但差异无显著性(P>0.05)。
2. FAK在实验组与对照组中的阳性表达率分别为73.91%、42.59%,FAK在实验组中的表达较对照组显著增高(p<0.01);Ezrin在实验组与对照组中的阳性表达率分别为78.26%、51.85%,Ezrin在实验组中的表达较对照组显著增高(p<0.01);
3. Paxillin在实验组与对照组中的阳性表达率分别为50.00%,40.74%,(p>0.05),Paxillin在实验组的表达较对照组增高,但差异无显著性(P>0.05)。
4. Integrinβ3在实验组与对照组中的阳性表达率分别为58.70%、33.33%,Integrinβ3在实验组中的表达较对照组显著增高(p<0.05);TrkC在实验组与对照组中的阳性表达率分别为50.00%、24.07%,TrkC在实验组中的表达较对照组显著增高(p<0.01)。
5.FAK、ERK、Ezrin的表达呈现彼此正相关的关系(P均<0.05)。
6.Integrinβ3的表达与Ezrin相关(P<0.01),但与ERK不相关(P>0.05)。
7.TrkC与ERK、Ezrin、FAK、Integrinβ3表达均无相关性(P>0.05)。
8.对临床病理因素包括发病年龄、肿瘤大小、腋淋巴结转移状态、pTNM分期进行寿命表法及单因素Kaplan-Meier法分析,结果显示:发病年龄、肿瘤大小、腋淋巴结转移状态、pTNM分期均与乳腺癌根治手术后复发转移率有关。
9.对十个实验指标包括ERK、JNK、FAK、Ezrin、Integrinβ3、TrkC、Paxillin、ER、PR、CerbB-2进行寿命表法及单因素Kaplan-Meier法分析,结果显示:ERK、FAK、Ezrin、Integrinβ3、TrkC、ER六个实验指标均与乳腺癌根治手术后复发转移率有关。
10.将单因素分析中与乳腺癌根治手术后复发转移有关的临床病理因素及实验指标包括发病年龄、肿瘤大小、腋淋巴结转移状态、pTNM分期、ERK、FAK、Ezrin、Integrinβ3、TrkC、ER共十个因素放入多因素COX模型中进行分析,结果显示:在α=0.05水平上,经逐步后退法筛选,逐步剔除pTNM分期、TrkC、肿瘤大小、腋淋巴结转移状态、发病年龄、Integrinβ3后,显示ER、FAK、ERK、Ezrin与乳腺癌根治手术后复发转移有关( P均<0.01 )。其中ER的B(相关系数)为-1.287,OR(比值比)为0.276; ERK、Ezrin、FAK的B依次为1.908、1.611、1.529,OR依次为6.742、5.007、4.611。
研究结论:
1.实验组中,ERK通路明显激活,JNK通路可能受抑制。ERK通路的激活、JNK通路受抑制在乳腺癌根治术后复发转移的发生中扮演了重要角色。
2.实验组中FAK、Ezrin、Integrinβ3、TrkC表达增高,受到激活,促进乳腺癌根治手术后复发转移。
3.实验组中Paxillin可能被激活,促进乳腺癌根治手术后复发转移。
4.实验组中ER表达降低,在乳腺癌根治手术后复发转移过程中受到抑制或拮抗。
5. FAK、Ezrin协同作用或与ERK结合成复合物,激活ERK/MAPK通路,促进乳腺癌根治手术后复发转移。
6. Integrinβ3与Ezrin有协同作用,促进乳腺癌根治手术后复发转移,但Integrinβ3的作用不是通过ERK/MAPK通路的激活实现的。
7.TrkC的表达促进乳腺癌根治手术后复发转移,TrkC的作用与ERK/MAPK通路的激活无关,可能与乳腺癌细胞的自分泌有关。
8.临床病理因素中,腋淋巴结转移、肿瘤大小>5 cm、发病年龄<40岁、临床分期Ⅲ期是乳腺癌根治手术后复发转移的危险因素。
9.实验指标中,FAK、ERK、Ezrin、Integrinβ3、TrkC是乳腺癌根治手术后复发转移的危险因素,ER是乳腺癌根治手术后复发转移的保护因素。
10.所有因素(包括临床病理因素和实验指标)中,FAK、ERK、Ezrin是乳腺癌根治手术后复发转移的独立危险因素,ER是乳腺癌根治手术后复发转移的独立保护因素。
OBJECTIVE:Mitogen-activated protein kinase(MAPK), including the extracellular signal- regulated protein kinase(ERK), the c-Jun N-terminal protein kinase(JNK) and et al, was an important signal transduction pathway of the cell, controlling cell malignant transformation, tumorigenesis and tumor proliferation. The analysis was to detect the expression of FAK, Ezrin, Paxillin, Integrinβ3, TrkC in 100 breast cancer cases, and to study the relationship between the expression of FAK, Ezrin, Paxillin, Integrinβ3, TrkC and ERK, JNK/MAPK signal transduction pathway in breast cancer with local recurrence and metastasis.
METHODS:All the 100 female breast cancer cases from the surgical department of the first affiliated hospital of Guang-Xi medical university and the first affiliated hospital of Guang-Xi tradional chinese medical university were collected. The clinical data and surgical information of the cases were got by follow-up survey. Two groups were established in the cases. One is experimental group, composing of 46 local recurrence and metastasis cases. The other is control group, composing of 54 tumor-free survival cases which have similar operative time and age. All the cases were treated by radical operation between 1994 and 2006 in the two hospitals. The analysis through immuno- histochemistry method and in situ hybridization in paraffin block was to detect the expression of FAK, Ezrin, Paxillin, Integrinβ3, TrkC in experimental group and control group, and to study the clinical characteristics of experi- mental group and control group.
RESULTS:
1.Over-expression for ERK was observed in 29/46 ( 63.04% ) in experimental group, while 21/54(38.46%)in control group. Over-expression for ERK in experimental group was higher than that in control group obviously(P<0.05). Over-expression for JNK was observed in 28/46(60.87%)in experimental group, while 41/54(75.93%)in control group . Over-expression for JNK in experimental group was lower than that in control group without significant difference(P>0.05).
2.Over-expression for FAK was observed in 34/46 ( 73.91% ) in experimental group, while 23/54(32.59%)in control group . Over-expression for FAK in experimental group was higher than that in control group obviously(P<0.01). Over-expression for Ezrin was observed in 36/46(78.26%)in experimental group, while 28/54(51.85%)in control group . Over-expression for Ezrin in experimental group was higher than that in control group obviously(P<0.01).
3. Over-expression for Paxillin was observed in 23/46(50.00%)in experimental group, while 22/54(40.74%)in control group. Over-expression for Paxillin in experimental group was higher than that in control group without significant difference(P>0.05).
4. Over-expression for Integrinβ3 was observed in 27/46(58.70%)in experimental group, while 18/54(33.33%)in control group. Over-expression for Integrinβ3 in experimental group was higher than that in control group obviously(P<0.05). Over-expression for TrkC was observed in 23/46 (50.00%)in experimental group, while 13/54(24.07%)in control group. Over- expression for TrkC in experimental group was higher than that in control group obviously(P<0.01).
5. Over-expression for ERK, FAK, Ezrin were positively correlated each other in the 100 cases(P<0.05).
6. Over-expression for Integrinβ3 was positively correlated with that for Ezrin in the 100 cases(P<0.01). Over-expression for Integrinβ3 was not correlated with that for ERK in the 100 cases(P>0.05).
7. Over-expression for ERK was not correlated with that for TrkC in the 100 cases(P>0.05). So did over-expression for Ezrin, FAK, Integrinβ3.
8.The results of the univariate analysis based on survival table and Kaplan-Meier method for clinical factors showed that the incidence age, the size of tumor, the status of axillary lymph node, the pTNM stage were related to the rate of local recurrence and metastasis after radical operation in breast cancer cases respectively.
9.The results of the univariate analysis based on Kaplan-Meier method for experimental factors showed that ERK, FAK, Ezrin, Integrinβ3, TrkC, ER were related to the rate of local recurrence and metastasis after radical operation in breast cancer cases respectively.
10. All the 10 factors related to local recurrence and metastasis after radical operation in breast cancer cases, including the incidence age, the size of tumor, the status of axillary lymph node, the pTNM stage, ERK, FAK, Ezrin, Integrinβ3, TrkC, ER, entered multivariate analysis by Cox regression to reject confounding factors. Backward gradually method used in Cox regression show that ERK, FAK, Ezrin, ER were related to local recurrence and metastasis after radical operation in breast cancer cases respectively ( P < 0.01 ) . The B(Correlation Coefficient) for ER was -1.287. The OR for ER was 0.276; The B for ERK, Ezrin, FAK were in sequence of 1.908, 1.611, 1.529. The OR for ERK, Ezrin, FAK were in sequence of 6.742, 5.007, 4.611.
CONCLUSIONS:
1. ERK signal pathway was activated obviously in experimental group, while JNK signal pathway might be suppressed. The activity of ERK signal transduction pathway and the suppression of JNK signal transduction pathway act as crucial roles for local recurrence and metastasis after radical operation in breast cancer cases in our opinion.
2. Over-expression of FAK, Ezrin, Integrinβ3, TrkC were higher in experimental group, showing that FAK, Ezrin, Integrinβ3, TrkC were acti- vated. The activity of FAK, Ezrin, Integrinβ3, TrkC promoted the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
3. Over-expression of Paxillin was higher in experimental group, showing that Paxillin might be activated. The activity of Paxillin might promote the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
4. Over-expression of was lower in experimental group, showing that ER might be suppressed or antagonized during the process of local recurrence and metastasis after radical operation in breast cancer cases.
5. Synergistic effect of FAK and Ezrin activated the ERK/MAPK signal transduction pathway, promoting the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
6. Synergistic effect of Integrinβ3 and Ezrin without activating the ERK/MAPK signal transduction pathway, promoted the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
7. The over-expression of TrkC without activating the ERK/MAPK signal transduction pathway, promoted the incidence for local recurrence and metastasis after radical operation in breast cancer cases through the autocrine loop of the breast cancer cells.
8. The status of axillary lymph node, the size of tumor, of the incidence age, the pTNM stage were risk factors for the incidence for local recurrence and metastasis after radical mastectomy in breast cancer cases in all clinical factors being related to local recurrence and metastasis of post-operational breast cancer.
9. ERK, FAK, Ezrin, Integrinβ3, TrkC were risk factors for the incidence for local recurrence and metastasis after radical operation in breast cancer cases in all experimental factors being related to local recurrence and metastasis of post-operational breast cancer, while ER was a protective factor.
10. ERK, FAK, Ezrin were independent risk factors for the incidence for local recurrence and metastasis after radical operation in breast cancer cases in all clinical and experimental factors being related to local recurrence and metastasis of post-operational breast cancer, while ER was a independent protective factor.
研究方法:收集1994-2006年广西医科大学第一附属医院外科及广西中医学院第一附属医院外科住院的女性乳腺癌患者共100例,收集临床资料,通过电话或通信随访,获得复发及生存情况。100例病人分成两个组:实验组为乳腺癌根治术后半年以上出现复发转移者共46例,标本取自1994-2006年在该两所医院手术并有完整的临床资料的患者,对照组为手术时间相近、发病年龄相近的乳腺癌根治术后未发生复发转移者共54例。石蜡封存组织块切片,应用免疫组织化学和核酸原位杂交技术,检测ERK、JNK、FAK、Integrinβ3、Paxillin、Ezrin、TrkC、ER、PR、CerbB-2在实验组、对照组的表达情况,并对实验组、对照组的临床病理因素进行研究。
研究结果:
1.ERK在实验组(复发转移组)与对照组(无复发转移组)中的阳性表达率分别为63.04%、38.89%,ERK在实验组中的表达较对照组显著增高(P<0.05);JNK在实验组与对照组中的阳性表达率分别为60.87%,75.93%(p>0.05),JNK在对照组中表达较与实验组高,但差异无显著性(P>0.05)。
2. FAK在实验组与对照组中的阳性表达率分别为73.91%、42.59%,FAK在实验组中的表达较对照组显著增高(p<0.01);Ezrin在实验组与对照组中的阳性表达率分别为78.26%、51.85%,Ezrin在实验组中的表达较对照组显著增高(p<0.01);
3. Paxillin在实验组与对照组中的阳性表达率分别为50.00%,40.74%,(p>0.05),Paxillin在实验组的表达较对照组增高,但差异无显著性(P>0.05)。
4. Integrinβ3在实验组与对照组中的阳性表达率分别为58.70%、33.33%,Integrinβ3在实验组中的表达较对照组显著增高(p<0.05);TrkC在实验组与对照组中的阳性表达率分别为50.00%、24.07%,TrkC在实验组中的表达较对照组显著增高(p<0.01)。
5.FAK、ERK、Ezrin的表达呈现彼此正相关的关系(P均<0.05)。
6.Integrinβ3的表达与Ezrin相关(P<0.01),但与ERK不相关(P>0.05)。
7.TrkC与ERK、Ezrin、FAK、Integrinβ3表达均无相关性(P>0.05)。
8.对临床病理因素包括发病年龄、肿瘤大小、腋淋巴结转移状态、pTNM分期进行寿命表法及单因素Kaplan-Meier法分析,结果显示:发病年龄、肿瘤大小、腋淋巴结转移状态、pTNM分期均与乳腺癌根治手术后复发转移率有关。
9.对十个实验指标包括ERK、JNK、FAK、Ezrin、Integrinβ3、TrkC、Paxillin、ER、PR、CerbB-2进行寿命表法及单因素Kaplan-Meier法分析,结果显示:ERK、FAK、Ezrin、Integrinβ3、TrkC、ER六个实验指标均与乳腺癌根治手术后复发转移率有关。
10.将单因素分析中与乳腺癌根治手术后复发转移有关的临床病理因素及实验指标包括发病年龄、肿瘤大小、腋淋巴结转移状态、pTNM分期、ERK、FAK、Ezrin、Integrinβ3、TrkC、ER共十个因素放入多因素COX模型中进行分析,结果显示:在α=0.05水平上,经逐步后退法筛选,逐步剔除pTNM分期、TrkC、肿瘤大小、腋淋巴结转移状态、发病年龄、Integrinβ3后,显示ER、FAK、ERK、Ezrin与乳腺癌根治手术后复发转移有关( P均<0.01 )。其中ER的B(相关系数)为-1.287,OR(比值比)为0.276; ERK、Ezrin、FAK的B依次为1.908、1.611、1.529,OR依次为6.742、5.007、4.611。
研究结论:
1.实验组中,ERK通路明显激活,JNK通路可能受抑制。ERK通路的激活、JNK通路受抑制在乳腺癌根治术后复发转移的发生中扮演了重要角色。
2.实验组中FAK、Ezrin、Integrinβ3、TrkC表达增高,受到激活,促进乳腺癌根治手术后复发转移。
3.实验组中Paxillin可能被激活,促进乳腺癌根治手术后复发转移。
4.实验组中ER表达降低,在乳腺癌根治手术后复发转移过程中受到抑制或拮抗。
5. FAK、Ezrin协同作用或与ERK结合成复合物,激活ERK/MAPK通路,促进乳腺癌根治手术后复发转移。
6. Integrinβ3与Ezrin有协同作用,促进乳腺癌根治手术后复发转移,但Integrinβ3的作用不是通过ERK/MAPK通路的激活实现的。
7.TrkC的表达促进乳腺癌根治手术后复发转移,TrkC的作用与ERK/MAPK通路的激活无关,可能与乳腺癌细胞的自分泌有关。
8.临床病理因素中,腋淋巴结转移、肿瘤大小>5 cm、发病年龄<40岁、临床分期Ⅲ期是乳腺癌根治手术后复发转移的危险因素。
9.实验指标中,FAK、ERK、Ezrin、Integrinβ3、TrkC是乳腺癌根治手术后复发转移的危险因素,ER是乳腺癌根治手术后复发转移的保护因素。
10.所有因素(包括临床病理因素和实验指标)中,FAK、ERK、Ezrin是乳腺癌根治手术后复发转移的独立危险因素,ER是乳腺癌根治手术后复发转移的独立保护因素。
OBJECTIVE:Mitogen-activated protein kinase(MAPK), including the extracellular signal- regulated protein kinase(ERK), the c-Jun N-terminal protein kinase(JNK) and et al, was an important signal transduction pathway of the cell, controlling cell malignant transformation, tumorigenesis and tumor proliferation. The analysis was to detect the expression of FAK, Ezrin, Paxillin, Integrinβ3, TrkC in 100 breast cancer cases, and to study the relationship between the expression of FAK, Ezrin, Paxillin, Integrinβ3, TrkC and ERK, JNK/MAPK signal transduction pathway in breast cancer with local recurrence and metastasis.
METHODS:All the 100 female breast cancer cases from the surgical department of the first affiliated hospital of Guang-Xi medical university and the first affiliated hospital of Guang-Xi tradional chinese medical university were collected. The clinical data and surgical information of the cases were got by follow-up survey. Two groups were established in the cases. One is experimental group, composing of 46 local recurrence and metastasis cases. The other is control group, composing of 54 tumor-free survival cases which have similar operative time and age. All the cases were treated by radical operation between 1994 and 2006 in the two hospitals. The analysis through immuno- histochemistry method and in situ hybridization in paraffin block was to detect the expression of FAK, Ezrin, Paxillin, Integrinβ3, TrkC in experimental group and control group, and to study the clinical characteristics of experi- mental group and control group.
RESULTS:
1.Over-expression for ERK was observed in 29/46 ( 63.04% ) in experimental group, while 21/54(38.46%)in control group. Over-expression for ERK in experimental group was higher than that in control group obviously(P<0.05). Over-expression for JNK was observed in 28/46(60.87%)in experimental group, while 41/54(75.93%)in control group . Over-expression for JNK in experimental group was lower than that in control group without significant difference(P>0.05).
2.Over-expression for FAK was observed in 34/46 ( 73.91% ) in experimental group, while 23/54(32.59%)in control group . Over-expression for FAK in experimental group was higher than that in control group obviously(P<0.01). Over-expression for Ezrin was observed in 36/46(78.26%)in experimental group, while 28/54(51.85%)in control group . Over-expression for Ezrin in experimental group was higher than that in control group obviously(P<0.01).
3. Over-expression for Paxillin was observed in 23/46(50.00%)in experimental group, while 22/54(40.74%)in control group. Over-expression for Paxillin in experimental group was higher than that in control group without significant difference(P>0.05).
4. Over-expression for Integrinβ3 was observed in 27/46(58.70%)in experimental group, while 18/54(33.33%)in control group. Over-expression for Integrinβ3 in experimental group was higher than that in control group obviously(P<0.05). Over-expression for TrkC was observed in 23/46 (50.00%)in experimental group, while 13/54(24.07%)in control group. Over- expression for TrkC in experimental group was higher than that in control group obviously(P<0.01).
5. Over-expression for ERK, FAK, Ezrin were positively correlated each other in the 100 cases(P<0.05).
6. Over-expression for Integrinβ3 was positively correlated with that for Ezrin in the 100 cases(P<0.01). Over-expression for Integrinβ3 was not correlated with that for ERK in the 100 cases(P>0.05).
7. Over-expression for ERK was not correlated with that for TrkC in the 100 cases(P>0.05). So did over-expression for Ezrin, FAK, Integrinβ3.
8.The results of the univariate analysis based on survival table and Kaplan-Meier method for clinical factors showed that the incidence age, the size of tumor, the status of axillary lymph node, the pTNM stage were related to the rate of local recurrence and metastasis after radical operation in breast cancer cases respectively.
9.The results of the univariate analysis based on Kaplan-Meier method for experimental factors showed that ERK, FAK, Ezrin, Integrinβ3, TrkC, ER were related to the rate of local recurrence and metastasis after radical operation in breast cancer cases respectively.
10. All the 10 factors related to local recurrence and metastasis after radical operation in breast cancer cases, including the incidence age, the size of tumor, the status of axillary lymph node, the pTNM stage, ERK, FAK, Ezrin, Integrinβ3, TrkC, ER, entered multivariate analysis by Cox regression to reject confounding factors. Backward gradually method used in Cox regression show that ERK, FAK, Ezrin, ER were related to local recurrence and metastasis after radical operation in breast cancer cases respectively ( P < 0.01 ) . The B(Correlation Coefficient) for ER was -1.287. The OR for ER was 0.276; The B for ERK, Ezrin, FAK were in sequence of 1.908, 1.611, 1.529. The OR for ERK, Ezrin, FAK were in sequence of 6.742, 5.007, 4.611.
CONCLUSIONS:
1. ERK signal pathway was activated obviously in experimental group, while JNK signal pathway might be suppressed. The activity of ERK signal transduction pathway and the suppression of JNK signal transduction pathway act as crucial roles for local recurrence and metastasis after radical operation in breast cancer cases in our opinion.
2. Over-expression of FAK, Ezrin, Integrinβ3, TrkC were higher in experimental group, showing that FAK, Ezrin, Integrinβ3, TrkC were acti- vated. The activity of FAK, Ezrin, Integrinβ3, TrkC promoted the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
3. Over-expression of Paxillin was higher in experimental group, showing that Paxillin might be activated. The activity of Paxillin might promote the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
4. Over-expression of was lower in experimental group, showing that ER might be suppressed or antagonized during the process of local recurrence and metastasis after radical operation in breast cancer cases.
5. Synergistic effect of FAK and Ezrin activated the ERK/MAPK signal transduction pathway, promoting the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
6. Synergistic effect of Integrinβ3 and Ezrin without activating the ERK/MAPK signal transduction pathway, promoted the incidence for local recurrence and metastasis after radical operation in breast cancer cases.
7. The over-expression of TrkC without activating the ERK/MAPK signal transduction pathway, promoted the incidence for local recurrence and metastasis after radical operation in breast cancer cases through the autocrine loop of the breast cancer cells.
8. The status of axillary lymph node, the size of tumor, of the incidence age, the pTNM stage were risk factors for the incidence for local recurrence and metastasis after radical mastectomy in breast cancer cases in all clinical factors being related to local recurrence and metastasis of post-operational breast cancer.
9. ERK, FAK, Ezrin, Integrinβ3, TrkC were risk factors for the incidence for local recurrence and metastasis after radical operation in breast cancer cases in all experimental factors being related to local recurrence and metastasis of post-operational breast cancer, while ER was a protective factor.
10. ERK, FAK, Ezrin were independent risk factors for the incidence for local recurrence and metastasis after radical operation in breast cancer cases in all clinical and experimental factors being related to local recurrence and metastasis of post-operational breast cancer, while ER was a independent protective factor.
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