| Background All over the world,breast cancer has become the biggest threat to woman's health,which has the highest incidence.About 1.4 million new cases occur each year,of which approximate 500000 die of this disease.In recent years,the incidence of breast cancer has been gradually increasing in the world.The age of patients with breast cancer tends to become younger.Breast cancer prone to brain metastases,the incidence is just behind lung.The statistics show that approximate 10%-16% of patients with advanced breast cancer will occur brain metastases,on the other hand,autopsy confirmed that the incidence of brain metastases is about 30%.After developing to brain metastases,the prognosis is very poor,the average survival time is about 1-2 months without any treatment,it will not more than 2 years after active treatment.Many clinical and pathological factors can affect the occurrence,development and prognosis of patients with brain metastases from breast cancer.Previous literatures summarize the relevant clinical and pathological factors,but the conclusions are not the same.In order to analyze the clinicopathological and prognostic factors of breast cancer brain metastases deeply and comprehensively,we collected the clinical and pathological data of 667 patients with breast cancer,analyzed the related indicators,and explored the effect of age and biological subtypes on the incidence of brain metastases from breast cancer.Further more,we collected the clinical and pathological data of 50 patients with brain metastases from breast cancer,summarized the characteristics on breast cancer brain metastases and discussed the prognostic factors affecting the survival time of BCBM,so that we could provide some reference for clinical treatment.AEG-1 is an oncogene that is closely related to the formation,invasion,progression and metastasis of many kind of tumors.Related studies have shown that AEG-1 is overexpressed in many kinds of malignant tumors,while,has low or no expression in normal tissues.Some studies have shown that AEG-1 plays an important role in the directional metastasis of breast cancer,it may participate in the regulation of the directional movement.CXCR4 is a chemokine receptor that is involved in the homing and transmission of the immune cells.In recent years,it has been found that CXCR4 is expressed in various tumor tissues and plays an important role in the process of tumor proliferation,invasion,vascularization and metastasis.Some studies have shown that CXCR4 has a higher level of expression in breast cancer tissues,which suggesting that high CXCR4 expression is related to the progression and metastasis of breast cancer.Until now,the molecular mechanism of brain metastases from breast cancer remains unclear.AEG-1 and CXCR4 may be related to the development of brain metastases from breast cancer.Therefore,we explore the role of AEG-1 and CXCR4 in the development of brain metastases from breast cancer.Additionally,to investigate the relationship between the expression of AEG-1 and CXCR4 and the related clinicopathologic factors in patients with brain metastases from breast cancer,and to clarify the role of AEG-1 and CXCR4 abnormal expression in the occurrence and development of brain metastases from breast cancer,so that it is possible to provide reference for predicting the relevant features of brain metastases developing from breast cancer.Chapter one: Effect of age and biological subtypes on the risk of brain metastases from breast cancer1.Aim To analyze the clinicopathological features of patients with breast cancer,explore the impact of age and biological subtypes on the incidence of brain metastases from breast cancer,and jointly analyze the significance of age and biological subtypes in predicting the occurrence of brain metastases from breast cancer,and provide reference for early clinical intervention.2.Methods The clinical and pathological data of 667 patients with breast cancer who were admitted to the Fifth Affiliated Hospital of Zhengzhou University from January 1,2003 to December 31,2013 was collected retrospectively,including the age,TNM-stage,histological grade,biological subtypes,treatments and something about brain metastases.The expression of ER,PR,and Her-2 was measured by immunohistochemistry analysis.The comparison between the percentage data was statistically analyzed using ?2 test.3.Results 1)The percentage of age group(>40)was 59.1% when diagnosed with breast cancer.TNM-staging included I(38.8%),II(48.6%),III(7.9%),IV(4.6%).The number of patients with lymph node metastasis was less than those without lymph node metastasis(44.8%?55.2%).The patients with hormone receptors ER+,PR+,and Her-2+ decreased in turn(63.3%?59.1%?24.3%),and the proportion of Her-2+ patients was the least.As for the biological subtypes,the percentage of Her-2 overexpression was the lowest(12.9%),followed by TNBC(17.1%),and the Luminal A was the most(49.1%).Most patients received the surgical treatment(97%).2)There were significant differences in the incidence of brain metastases from breast cancer with different biological subtypes(P<0.05),whereas,there was no significant difference in the incidence of brain metastases between patients ?40 years old and >40 years old(P>0.05).3)There were significant differences in the incidence of brain metastases among different biological subtypes in different age groups(P<0.05).There was no significant difference in the incidence of brain metastases among the breast cancer patients with ?40 years.However,for the patients with >40 years,the incidence of brain metastases with TNBC and Her-2 overexpression was significantly higher than those with Luminal subtype(P<0.05).Taking both the age and biological subtypes into consideration,the incidence of brain metastases from the breast cancer patients with TNBC and Her-2 overexpression subtype in the 40-year-old group was significantly higher than those ? 40-year-old group,and the difference was statistically significant(P<0.05).4.Conclusions 1)Age is not the factor affecting the incidence of brain metastases in breast cancer patients with Luminal A and Luminal B,but there are significant differences in the incidence of brain metastases among patients of different age groups for patients with TNBC and Her-2 overexpression subtype.2)Biological subtypes play a significant effect on the occurrence of brain metastases from breast cancer.Patients with TNBC and Her-2 overexpression subtypes are more easy to develop to brain metastasis than those with Luminal subtype.Chapter two: Analysis of clinicopathological features and predictors about survival of 50 cases with brain metastases from breast cancer1.Aim 50 patients with brain metastases from breast cancer diagnosed at the Fifth Affiliated Hospital of Zhengzhou University between 2003 and 2013 were retrospectively evaluated.To find out the relationship between the development of brain metastasis and the factors as well as the predictors of survival.2.Methods The clinicopathological data of 50 patients with brain metastases from breast cancer diagnosed at the Fifth Affiliated Hospital of Zhengzhou University from January 2003 to December 2013 were retrospectively collected.The factors such as General conditions,histological grade,TNM stage,KPS score,molecular subtype,pathological type,menopausal status,metastatic site,number of brain metastases,serum tumor markers,therapies and so on are included.The clinical features are summarized.The factors affecting the development of brain metastasis,the survival time after brain metastasis and the survival rate are analyzed.3.Results 1)The age range was 25-76 years old when patients with breast cancer brain metastases were diagnosed with breast cancer,and the median age was 46 years old.Most of the patients were older than 40 years.As for TNM-staging,there were many patients with stage-II and stage-III(34%,40%),No.of stage-I was the least(12%).Stag-IV was little than stage-I and II(14%).The percentage of patients with histological grade 3 was 64%;In terms of biological subtypes,TNBC accounted for the highest proportion(34%),and patients with Luminal A,Luminal B,Her-2 overexpressed decreased in turn.The main pathological type was invasive ductal carcinoma(72%).Patients with the simple brain metastases were few,and most of them were accompanied by viscera and other parts metastases(26%,74%).Patients with three or more metastases were the major group(70%).Most patients had a KPS score of more than 60(72%).As for tumor markers,there was no significant difference in the distribution of CEA and CA153 level.However,the proportions of patients with BCBM with CA125 ?35U/ml differed from those with CA125 >35U/ml significantly(58%,42%).2)Median TTBM was 26.8 months(range between 0-153.6 months),and median BMFS was 6.8 months(range between 0-38.9 months).TTBM was influenced by pathological type,TNM stage,histological grade and the molecular type. No clinicopathological factors affected the BMFS.3)The median survival time of the patients newly diagnosed with brain metastases was 8.8 months(range 0.6-41.7 months).The one-year survival rate was 37.2%,the two-year survival rate was 16.5%.Univariate analysis showed some statistically significant factors such as histological grade,number of brain metastases,KPS score,CEA,CA125 level,and molecular classification at BM(P<0.05).4)Multivariate Cox analysis showed that the number of brain metastases,molecular classification of breast cancer,KPS score,CEA level and treating ways at BM were the independent prognostic factors for overall survival(P<0.05).4.Conclusions 1)Time to develop brain metastases is affected by pathological type,histological grade,molecular type and TNM-staging.2)Surgical resection and comprehensive treatment for patients with brain metastases from breast cancer are the firs-line therapies.3)Number of brain metastases,molecular classification,KPS score,serum CEA level and treating ways are independent prognostic factors for patients with BCBM.Less brain metastases,KPS score?60,CEA expressing level under 5ng/ml,molecular type(Luminal type)may improve patients prognosis.Surgical resection and comprehensive treatment can improve survival.Chapter three: Mechanisms of AEG-1 and CXCR4 gene expression regulating the epithelial-mesenchymal transition pathway involved in brain metastases of breast cancer1.Aim To study the astrocyte elevated gene(AEG-1)in breast cancer and the mechanism of chemokine receptor CXCR4 regulating the epithelial-mesenchymal transition(EMT)involved in brain metastases from breast cancer.2.Methods 1)A total of 30 breast cancer patients with brain metastases and 40 without brain metastases diagnosed in the Fifth Affiliated Hospital of Zhengzhou University were recruited.The pathological data of every patient were collected.The cancer tissue and adjacent normal tissue were collected.Three specimens from the cancer tissue were produced randomly,the same with the adjacent normal tissue.The group with BCBM had a total of 180 specimens,the group with BC had 240 specimens.2)The expression of AEG-1,CXCR4,E-cadherin,N-cadherin,and ?-SMA were detected by immunohistochemistry analysis,real-time quantitative PCR and Western blot respectively in cancer and adjacent normal tissues.3.Results 1)Immunohistochemical staining showed that the positive expression rate of AEG-1,CXCR4,N-cadherin,and ?-SMA in the cancer tissues of patients with brain metastases from breast cancer was higher those without brain metastases,while the E-cadherin was lower than those without brain metastases.There was no significant difference in the adjacent normal tissues from both groups.2)RT-PCR indicated that the expression of AEG-1,CXCR4,N-cadherin,and ?-SMA in the cancer tissues of patients with brain metastases from breast cancer were higher than those without brain metastases,while,the expression of E-cadherin m RNA was lower than those without brain metastases.There was no significant difference in m RNA expression in the adjacent normal tissues from both groups.3)Western blot analysis showed that the expression of the protein about AEG-1,CXCR4,N-cadherin,and ?-SMA in the cancer tissues of patients with brainmetastases were higher than those without brain metastases,while,the protein expression of E-cadherin was lower than those without brain metastases.There was no significant difference in protein expression in the adjacent normal tissues from both groups.4.Conclusions AEG-1 and CXCR4 are closely related to the occurrence and development of brain metastases from breast cancer,which may promote the invasion and metastasis of breast cancer cells into brain tissue.EMT pathway is an important part in the process of brain metastasis from breast cancer.AEG-1 and CXCR4 may activate and regulate the EMT pathway to participate in the process of brain metastasis from breast cancer.Chapter four: Correlation between the expression of AEG-1 and CXCR4 and the clinicopathological factors of patients with brain metastases from breast cancer1.Aim To investigate the expression of AEG-1 and CXCR4 in the primary breast cancer tissues of patients with breast cancer brain metastases(BCBM),and to explore the relationship between the expression of AEG-1 and CXCR4 and its clinicopathologic factors,so that to determine the value of AEG-1 and CXCR4 in predicting the characteristics and overall prognosis of BCBM.2.Methods The clinical and pathological data of 50 patients with brain metastases developing from the primary breast cancer who received diagnosis and treatment in the department of neurosurgery and breast surgery in the Fifth Affiliated Hospital of Zhengzhou University from 2003 to 2013 was collected retrospectively.Some factors such as the patient's age,TNM-staging,histological grade,histological type of breast cancer,biological subtypes,time of brain metastases developing from breast cancer,the number of brain metastases,KPS scores and so on were included.The specimens from primary breast cancer tissue and adjacent normal tissue were obtained successfully.The expression of AEG-1 and CXCR4 of the breast cancer tissues and adjacent normal tissues was detected by immunohistochemistry analysis.Using ?2 test or Fisher's exact method to test the positive rate of AEG-1 and CXCR4.Applying Spearmen Rank test to analyze the correlation of data.3.Results 1)AEG-1 was mainly expressed in the cytoplasm or the cell membrane,which showed brown-yellow granules.The positive expression rate of AEG-1 in the breast cancer tissues was significantly higher than that in adjacent normal tissues(?2=27.4,P<0.001).The positive expression of CXCR4 mainly showed that either the cytoplasm or the nucleus was stained,sometimes,it was found that both the cytoplasm and nucleus were stained.The brown-yellow particles were observed.The positive expression rate of CXCR4 in the cancer tissues was significantly higher than that in the adjacent normal tissues(?2=21.58,P<0.001).2)The positive expression rate of AEG-1 and CXCR4 of patients with BCBM were 76% and 66%,respectively.The expression level of AGE-1 and CXCR4 was significantly associated with the TNM-staging,biological subtypes,lymph node metastasis,No.of the brain metastases,and the time of brain metastases developing from breast cancer(P<0.05).However,it was not related to patient's age,histological grade of tumor,pathological types,and KPS scores(P>0.05).3)The relative expression quantities in the primary breast cancer tissues of patients with BCBM between AEG-1 and CXCR4 demonstrated positive correlation(r=0.577,P=0.024).4.Conclusions 1)The up-regulation of AEG-1 and CXCR4 expression correlates with the incidence of BCBM,which may have the potential value in predicting something about the characteristics of brain metastases from breast cancer.It may be used as a potential intervention target to decrease the incidence of BCBM.2)There is significant difference between the expression of AEG-1 and CXCR4 in the primary breast cancer tissues of patients with BCBM and some factors such as lymph node metastasis,TNM-staging,biological subtypes,No.of brain metastases,time of brain metastases developing from breast cancer and so on,which indicates that the abnormalities of expression of the AEG-1 and CXCR4 plays an important part in the occurrence and development of BCBM.3)AEG-1 and CXCR4 may participate in the development of brain metastases from breast cancer together through some links. |
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