Analysis Of FAK, Ezrin, Paxillin, Integrin β3, TrkC And The Activation Or Suppression Of ERK,JNK/MAPK Signal Transduction Pathway

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.