Mechanism Of Interaction Between ERβ And ER Signal Transduction Path-MAPK In Breast Cancer Of Mice

Objective:To investigate what effect estrogen,estrogen-receptor-antagon and Cytoxan could make on ERβand ER singnal transduction path--MAPK by utilizing mouse breast cancer modal-BCML-TA299,to approach initially the protein expression dependability between ERβand the key enzyme--MEK-2 and p-ERK in MAPK singnal transduction path,thereby,to try to explain the mechanism of interaction between ERβand this path in the course of breast cancer development and apoptosis.Methods:To divide the mice into 5 groups:control group,TAM group,E2 group, CTX group and combination group(TAM+CTX).On the basis of breast cancer orthotopic transplation,we supplied TAM,E2 and CTX to interfere in each trail group,then to observe dynamicly the transformation of cell morphology at different time,detect and contrast the expression level of ERβ,MEK-2 and p-ERK in breast cancer cells with immunohistochemistry,detect the change of cell cycle and apoptosis with FCM.The control group,TAM group and CTX group mice were inject radioactive nuclide Sm-153(2ug/lmCi)through vena caudalis and then made cells apoptosis develop by the method of circum-DTPA.Results:The growth phase of BCML-TA299 orthotopic transplantation tumor could be divided into three phases,latency phase(1-10days):tumor grew very slowly; exponent growth phase(11-20):tumor grew fast,the size almost raised 7-10 times; stable growth phase(21-30):the tumor size continued to increase,but the increasing speed was slow.During the early and middle stages,there was not instinct difference of tumor size among the control,TAM and E2groups,but the E2 group tumor size was bigger than the others until advanced stage(P＜0.01).Tumor in CTX and combination group grew slowly,their size especially the latter ones were smaller than the other three groups(P＜0.01);Tumor cells grew actively in control group and E2 group,playing invasive growth,caryocinesia could be observed,there were abundant blood vessels among tumor cells;Cancer cells showed various levels of focus necrosis in other groups,cell nuclear became swelling and cavitate,karyopycnosis, nuclear fragmentation and apoptotic body could be observed,especially in combination group.The pulmonary metastasis appeared late in TAM group,The pulmonary metastasis rate in E2 group was higher than in TAM group(P＜0.05);The three kinds of protein--ERβ,MEK-2 and p-ERK expressed in each group cancer cells, the expressing rate was 100%;E2 could activate and elevate these protein expression; TAM and CTX could inhibit these protein expression,especially combining action(P＜0.01);ERβprotein expression displayed positive correlation with MEK-2 and p-ERK,that is,these three kinds of protein showed coordinate expression;E2 could promote tumor cells convert from G1 stage to S stage,so that lead to cancer cells proliferation and tumor advancement;TAM and CTX could make tumor cells detent at G1 stage,inhibit cancer cells proliferation and promote apoptosis to appear.It showed apoptotic peak on the left of G0 phase in TAM group and combination group, the apoptotic rate were 2.3%and 13.1%respectively,this result was matched with the cancer cells apoptosis develop.Conclusions:E2 could promote tumor cells to grow and metastasis to appear by activationg ERβand the key enzyme in MAPK;TAM and CTX could resist tumor to progress by rivaling and down regulating the expression of ERβ,MEK-2 and p-ERK, meanwhile could promote apoptosis to occur;TAM could make synergistic effect on CTX;ERβand MAPK signal transduction path interact and influenced the development,apoptosis and endocrine therapy sensitivity of breast cancer,they may become the new targets of breast cancer therapy.