乳腺癌组织PAX2、AIB-1蛋白表达与临床病理指标及预后关系的研究
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摘要
目的：近年来，随着发病率逐年上升，乳腺癌已成为威胁女性健康的最重要的恶性肿瘤，而以他莫西芬为代表的内分泌治疗成为激素受体阳性乳腺癌最成功有效的治疗方法之一。因此，对于乳腺癌他莫西芬耐药的研究成为近年来的热点问题，有研究表明，在雌激素受体（Estrogen Receptor，ER）阳性的乳腺癌中，配对盒基因PAX2（Paired box gene2）和乳腺癌扩增因子AIB-1（Amplified in breast cancer-1）能够在他莫西芬治疗过程中调控人类表皮生长因子受体-2（ERBB2/Her-2）基因的转录水平，进而调控HER-2的蛋白表达，影响他莫西芬在ER阳性乳腺癌中治疗效果。本课题采用免疫组织化学链霉菌抗生物素蛋白-过氧化酶法（streptavidinperoxdase conjugated method，S-P）对88例乳腺癌术后ER阳性并接受正规他莫西芬治疗患者标本中PAX2和AIB-1的蛋白表达进行检测，分析两者的表达强度与ER阳性乳腺癌患者抗雌激素治疗耐药的关系，为乳腺癌内分泌治疗的合理选择和有效性预判提供新的指标。
方法：搜集乳腺癌术后病理证实为ER阳性，并接受他莫西芬(TAM)规范治疗患者肿瘤组织标本共88例，根据随访结果显示：5年无瘤生存（TAM治疗敏感）患者50例，5年内出现局部复发或远位转移（TAM耐药）患者38例，通过S-P法测定乳腺癌组织石蜡病理标本的PAX2和AIB-1蛋白表达水平，分析二者的量化关系，以及与复发转移率的关系，并按患者的临床病理资料：年龄、月经状况、肿瘤大小、临床分期、病理类型、组织学分级、腋淋巴结转移情况、ER、PR、HER-2等因素进行分层分析二者蛋白表达强度的差异。
运用SPSS13.0统计软件包中完全随机设计两样本率及多样本率比较的χ2检验，以α=0.05为检验水准。
结果：
1.随访结果：
88例乳腺癌患者术后5年内无瘤生存共50例；术后5年内出现局部复发或远位转移共38例，平均无病生存期（disease-free survival, DFS）45个月，平均总生存期（overall survival, OS）56个月。
2.PAX2蛋白表达强度与临床病理学特征的关系
88例乳腺癌患者按年龄分为两组（<50岁和≥50岁），经统计学分析，PAX2蛋白的高表达在不同年龄组间无统计学差异（χ~2=1.349；p=0.246），提示PAX2蛋白表达的高低与乳腺癌患者的年龄无关。
88例乳腺癌患者按月经状况分为两组（绝经前和绝经后），经统计学分析，PAX2蛋白的高表达在不同月经状况组间无统计学差异（χ~2=0.134；p=0.714），提示PAX2表达的高低与乳腺癌患者的月经状况无关。
88例乳腺癌患者按肿瘤大小分为两组（≤5cm和>5cm），经统计学分析，PAX2蛋白的高表达在不同肿瘤大小组间有统计学差异（χ~2=4.244；p=0.039），提示PAX2蛋白表达率在T>5cm组中较低。
88例乳腺癌患者按临床分期分为两组（I~II期和III期），经统计学分析，PAX2蛋白的高表达在不同临床分期组间无统计学差异（χ~2=0.243；p=0.622），提示PAX2蛋白表达的高低与乳腺癌患者的临床分期无关。
88例乳腺癌患者按病理学类型分为三组（浸润性导管癌、浸润性小叶癌和其他类型），经统计学分析，PAX2蛋白的高表达在不同病理学类型组间无统计学差异（χ~2=3.158；p=0.206），提示PAX2蛋白表达的高低与乳腺癌患者的病理类型无关。
88例乳腺癌患者按组织学分级分为两组（I~II级和III级），经统计学分析，PAX2蛋白的高表达在不同组织学分级组间无统计学差异（χ~2=0.085；p=0.771），提示PAX2表达的高低与乳腺癌患者的组织学分级无关。
88例乳腺癌患者按腋窝淋巴结转移状况分为两组（无转移，有转移），经统计学分析，PAX2蛋白的高表达在淋巴结转移状况组间无统计学差异（χ~2=0.477；p=0.490）。PAX2蛋白的高表达在淋巴结转移状况组间无统计学差异，按腋窝淋巴结转移个数分为三组（无转移，转移1~3个淋巴结和＞3个淋巴结），经统计学分析，PAX2蛋白的高表达率在淋巴结转移个数组间无统计学差异（χ~2=1.517；p=0.468），提示PAX2蛋白表达的高低与乳腺癌患者腋窝淋巴结转移无关。
88例乳腺癌患者按HER-2蛋白表达水平分为两组（低表达和高表达），经统计学分析， PAX2蛋白的高表达在不同HER-2蛋白表达水平组间有统计学差异（χ~2=5.301；p=0.021），提示PAX2蛋白在HER-2蛋白过表达乳腺癌患者中表达率较低。
88例乳腺癌患者按ER表达水平分为三组（+）、（++）和（+++），经统计学分析，PAX2蛋白的高表达在不同ER蛋白表达水平组间无统计学差异（χ~2=1.130；p=0.568），提示PAX2蛋白表达的高低与乳腺癌患者ER蛋白的表达无关。
88例乳腺癌患者按PR表达水平分为两组（阴性和阳性），经统计学分析，PAX2蛋白的高表达在不同PR表达组间无统计学差异（χ~2=0.488；p=0.485），提示PAX2蛋白表达的高低与乳腺癌患者PR蛋白的表达无关。
3．AIB-1蛋白表达与临床病理学特征的关系
88例乳腺癌组织按患者年龄分为两组（<50岁和≥50岁），经统计学分析， AIB-1蛋白的高表达在不同年龄组间无统计学差异（χ~2=0.549；p=0.459），提示AIB-1蛋白表达的高低与乳腺癌患者的年龄无关。
88例乳腺癌组织按患者月经状况分为两组（绝经前和绝经后），经统计学分析，AIB-1蛋白的高表达在不同月经状况组间无统计学差异（χ~2=0.074；p=0.785），提示AIB-1蛋白表达的高低与乳腺癌患者的月经状况无关。
88例乳腺癌组织按肿瘤直径分为两组（≤5cm和>5cm），经统计学分析，AIB-1蛋白的高表达在不同肿瘤大小组间无统计学差异（χ~2=0.433；p=0.511），考虑蛋白AIB-1蛋白表达的高低与乳腺癌患者的肿瘤大小无关。
88例乳腺癌患者按临床分期分为两组（I~II期和III期），经统计学分析，AIB-1蛋白的高表达在不同临床分期组间有统计学差异（χ~2=7.140；p=0.008），AIB-1蛋白在III期乳腺癌中表达率较高。
88例乳腺癌患者按病理学类型分为三组（浸润性导管癌、浸润性小叶癌和其他类型），经统计学分析，AIB-1蛋白的高表达在不同病理学类型组间无统计学差异（χ~2=2.214；p=0.331），提示AIB-1蛋白表达的高低与乳腺癌患者的病理类型无关。
88例乳腺癌患者按组织学分级分为两组（I~II级和III级），经统计学分析，AIB-1蛋白的高表达在不同组织学分级组间无统计学差异（χ~2=0.155；p=0.694），提示AIB-1蛋白表达的高低与乳腺癌患者的组织学分级无关。
88例乳腺癌患者按腋窝淋巴结转移状况分为两组（无转移，有转移），经统计学分析，AIB-1蛋白的高表达在淋巴结转移状况组间无统计学差异（χ~2=2.370；p=0.124）。按腋窝淋巴结转移个数分为三组（无转移，1~3个淋巴结转移和>3个淋巴结转移），经统计学分析，AIB-1蛋白的高表达在不同淋巴结转移个数组间无统计学差异（χ~2=2.399；p=0.301），提示AIB-1蛋白表达的高低与乳腺癌患者腋窝淋巴结转移无关。
88例乳腺癌患者按HER-2蛋白表达水平分为两组（低表达和高表达），经统计学分析，AIB-1蛋白的高表达在不同HER-2蛋白表达水平组间有统计学差异（χ~2=7.912；p=0.005），提示AIB-1蛋白在HER-2过表达组中表达率较高。
88例乳腺癌患者按ER蛋白表达水平分为两组（+）、（++）和（+++），经统计学分析，AIB-1蛋白的高表达在不同ER蛋白表达水平组间无统计学差异（χ~2=2.247；p=0.325），考虑AIB-1蛋白表达的高低与乳腺癌患者ER蛋白的表达无关。
88例乳腺癌患者按PR表达水平分为两组（阴性和阳性），经统计学分析，发现AIB-1蛋白的高表达在不同PR蛋白表达水平组间有统计学差异（χ~2=3.930；p=0.047），考虑AIB-1蛋白在PR蛋白阳性组中表达率较高。
4.乳腺癌复发转移状况与PAX2、AIB-1蛋白表达的关系：
88例乳腺癌患者中，经统计学分析，乳腺癌复发转移率在不同PAX2蛋白表达组中有统计学差异（χ~2=4.219；p=0.040），提示PAX2高表达患者复发转移率较低，预后较理想。
88例乳腺癌患者中，经统计学分析，复发转移率在不同AIB-1蛋白表达组中无统计学差异（χ~2=0.252；p=0.616），说明AIB-1蛋白表达水平对预后判定不敏感。
结论：
在乳腺癌术后ER阳性并接受他莫西芬(TAM)规范治疗患者中：
1. PAX2蛋白表达与乳腺癌患者年龄、月经状况、临床分期以及乳腺癌标本病理类型、组织学分级、淋巴结有无转移及转移个数、ER蛋白、PR蛋白表达水平等因素均无关，PAX2蛋白高表达在肿瘤直径T>5cm组中与HER-2蛋白过表达组中较低；
2. AIB-1蛋白表达与乳腺癌患者年龄、月经状况、肿瘤大小以及乳腺癌标本病理类型、组织学分级、淋巴结有无转移及转移个数、ER表达水平等因素均无关，AIB-1蛋白高表达在临床分期III期组、PR蛋白阳性组与HER-2蛋白过表达组中较高；
3. AIB-1蛋白表达对乳腺癌预后判定不敏感；PAX2蛋白高表达患者5年内复发转移率较低，预后较好。
Objective: In recent years, as a rising of incidence rate, breast cancer hadbecome the most important malignant tumors treated to women's health. Ithad become the most successful and effective treatment for hormonereceptor-positive breast cancer to assist endocrine therapy with representativeof tamoxifen. So in these years, the studis have foucs on the resistance oftamoxifen. Research have shown that PAX2（Paired box gene2） andAIB-1(Amplified in breast cancer-1) regulates the transcription level ofhuman epidermal growth factor receptor-2(ERBB2/Her-2) during thetreatment to estrogen receptor(ER)-postive breast cancer with tamoxifen.Further PAX2and AIB-1regulated the expression of HER-2protein, andinflunced the tamoxifen therapy of ER-positive breast cancer patients. In thisstudy, we detected the expression of PAX2and AIB-1protien of88ER-positive patients treated with tamoxifen (TAM) after modified radicalmastectomy with streptavidin peroxdase （S-P） conjugated method.Analysed the relationship between the expression levels anti-estrogentherapy resistance, and promted new indicators for the reasonable choice andvalidity determination of Endocrine therapy of breast cancer.
Methods: Collected88tumor tissue samples of ER-positive patientstreated with tamoxifen (TAM) after modified radical mastectomy.According to follow-up results within5years:50cases of patients were freesurvival (TAM sensitive), and38cases of patients appeared local recurrenceor distant metastasis (TAM-resistance). Detected the expression of PAX2andAIB-1protein of breast cancer tissues, analysed the quantitative relationshipbetween these two protein, and the correlation between the expression level ofPAX2, AIB-1and TAM treatment. In addition, contrast the difference between different groups according to a variety of factors, including age, menstrualstatus, clinical stage, diameter of the tumors, histology grade, state of themetastatic axillary lymph nodes, pathology type and the expression of ER, PR,HER-2on protein level.
All statistical analyses were performed with Chi-square test of SPSS13.0software. α=0.05was the size of the test．
Result：
1. Follow-up results:
Among88cases of breast cancer patients, there were50cases appearedtumor-free survival, while38cases appeared local recurrence or distantmetastasis within5years after surgery, with the mean disease-freesurvival(DFS) of20month and the mean overall survival(OS) of32month.
2. The relationship between the expression of PAX2protein and Clinical andpathological features.
88cases of breast cancer patients were divided into two groups accordingto the age(<50years and≥50years), the over-expression of PAX2proteinbetween them had no significant difference (χ~2=1.349, p=0.246)． Consideredthat the expression density of PAX2protein had no significant correlationbetween the age of the patients.
88cases of breast cancer patients were divided into two groups accordingto the menstrual status (premenopause and postmenopause), theover-expression of PAX2protein between them had no significant difference(χ~2=0.134, p=0.714)． Considered that the expression density of PAX2proteinhad no significant correlation between the menstrual status of the patients.
88cases of breast cancer patients were divided into two groups accordingto the diameter of the tumors (≤5cm and>5cm), the over-expression of PAX2protein between them had significant difference (χ~2=4.244,p=0.039)． Considered that the expression rate of PAX2protein was lower inthe group of T>5cm.
88cases of breast cancer patients were divided into two groups accordingto the clinical stage (stage I~II and III), the over-expression of PAX2protein between them had no significant difference (χ~2=0.243, p=0.622)． Consideredthat the expression density of PAX2protein had no significant correlationbetween the clinical stage of the patients.
88cases of breast cancer patients were divided into two groups accordingto the histological grade (grade I~II and III), the over-expression of PAX2protein between them had no significant difference (χ~2=0.085,p=0.771)． Considered that the expression density of PAX2protein had nosignificant correlation between the histological grade of the patients.
88cases of breast cancer patients were divided into two groups accordingto the state of the axillary lymph nodes (negative and positive), theover-expression of PAX2protein between them had no significant difference(χ~2=0.477, p=0.490). And we divided them into three groups according to thestate of the axillary lymph nodes (negative,1~3， and＞3), theover-expression of PAX2protein among them had no significant difference(χ~2=1.517, p=0.468)． Considered that the expression density of PAX2proteinhad no significant correlation between the state of the axillary lymph nodes ofthe patients.
88cases of breast cancer patients were divided into three groups accordingto the state of the pathological types (invasive ductal carcinoma, invasivelobular carcinoma and other), the over-expression of PAX2protein amongthem had no significant difference (χ~2=3.158, p=0.206)． Considered that theexpression density of PAX2protein had no significant correlation between thepathological types of the patients.
88cases of breast cancer patients were divided into two groups accordingto the expression level of HER-2(low-expression and over-expression), theover-expression of PAX2protein between them had significant difference(χ~2=5.301, p=0.021)． Considered that the expression level of PAX2protein islower in the group of over-expression of HER-2protien.
88cases of breast cancer patients were divided into two groups accordingto the expression level of ER (+),(++) and (+++), the over-expression ofPAX2protein between them had no significant difference (χ~2=1.130, p=0.568)． Considered that the expression density of PAX2protein had nosignificant correlation between the expression level of ER.
88cases of breast cancer patients were divided into two groups accordingto the expression level of PR (negative and positive), the over-expression ofPAX2protein between them had no significant difference (χ~2=0.488,p=0.485)． Considered that the expression density of PAX2protein had nosignificant correlation between the expression level of PR.
3. The relationship between the expression of AIB-1protein and Clinical andpathological features.
88cases of breast cancer patients were divided into two groups accordingto the age(<50years and≥50years), the over-expression of AIB-1proteinbetween them had no significant difference (χ~2=0.549, p=0.459)． Consideredthat the expression density of AIB-1protein had no significant correlationbetween the age of the patients.
88cases of breast cancer patients were divided into two groups accordingto the menstrual status (premenopause and postmenopause), theover-expression of AIB-1protein between them had no significant difference(χ~2=0.074, p=0.785)． Considered that the expression density of AIB-1proteinhad no significant correlation between the menstrual status of the patients.
88cases of breast cancer patients were divided into two groups accordingto the diameter of the tumors (≤5cm and>5cm), the over-expression of AIB-1protein between them had no significant difference (χ~2=0.433,p=0.511)． Considered that the expression density of AIB-1protein had nosignificant correlation between the diameter of the tumors of the patients..
88cases of breast cancer patients were divided into two groups accordingto the clinical stage (stage I~II and III), the over-expression of AIB-1proteinbetween them had no significant difference (χ~2=7.140, p=0.008)． Consideredthat the expression level of AIB-1protein is higher in the group of the clinicalstage III.
88cases of breast cancer patients were divided into two groups accordingto the histological grade (grade I~II and III), the over-expression of AIB-1 protein between them had no significant difference (χ~2=0.155,p=0.694)． Considered that the expression density of AIB-1protein had nosignificant correlation between the histological grade of the patients.
88cases of breast cancer patients were divided into two groups accordingto the state of the axillary lymph nodes(negative and positive), theover-expression of AIB-1protein among them had no significant difference(χ~2=2.370, p=0.124). And we divided them into three groups according to thestate of the axillary lymph nodes(negative,1~3，and>3), the over-expressionof AIB-1protein among them had no significant difference (χ~2=2.399,p=0.301)． Considered that the expression density of AIB-1protein had nosignificant correlation between the state of the axillary lymph nodes of thepatients.
88cases of breast cancer patients were divided into three groups accordingto the state of the pathological types (invasive ductal carcinoma, invasivelobular carcinoma and other), the over-expression of AIB-1protein amongthem had no significant difference (χ~2=2.214, p=0.331)． Considered that theexpression density of AIB-1protein had no significant correlation between thepathological types of the patients.
88cases of breast cancer patients were divided into two groups accordingto the expression level of HER-2(low-expression and over-expression), theover-expression of AIB-1protein between them had significant difference(χ~2=7.912, p=0.005)． Considered that the expression level of AIB-1protein islower in the group of over-expression of HER-2protein.
88cases of breast cancer patients were divided into two groups accordingto the expression level of ER (+),(++)and(+++), the over-expression of AIB-1protein between them had no significant difference (χ~2=2.247,p=0.325)． Considered that the expression density of AIB-1protein had nosignificant correlation between the expression level of ER protein.
88cases of breast cancer patients were divided into two groups accordingto the expression level of PR (negative and positive), the over-expression ofAIB-1protein between them had no significant difference (χ~2=3.930, p=0.047)． Considered that the expression level of AIB-1protein is higher inthe group of PR protein positive.
4. Relationship between PAX2protein, AIB-1protein and recurrence ormetastasis of breast cancer.
Among88cases of breast cancer,38cases appeared recurrence ormetastasis, while50cases were free survival within5years. After statisticalanalysis, recurrence or metastasis rate of breast cancer patients had nosignificant difference between different groups of expression of AIB-1protein(χ~2=0.252, p=0.616), while had significant difference between differentgroups of PAX2protein(χ~2=4.219, p=0.040). Considered that AIB-1proteinwas not sensitive for prognosis of TAM treatment, while recurrence ormetastasis rate of breast cancer patients was lower in the group ofover-expression of PAX2protein.
Conclusion：
Among88cases of the ER-positive breast cancer patients treated withtamoxifen (TAM)：
1. The expression of PAX2in the breast cancer tissues had no significantcorrelation with age, menstrual status, clinical stage, histology grade, state ofthe metastatic axillary lymph nodes, pathology type and the expression of ER,PR on protein level. The PAX2protein had lower over-expression rate in bothgroup of T>5cm and over-expression of HER-2protein.
2. The expression of AIB-1in the breast cancer tissues had no significantcorrelation with age, menstrual status, diameter of the tumors, histology grade,state of the metastatic axillary lymph nodes, pathology type and the expressionof ER protein. The AIB-1protein had higher over-expression rate in bothgroup of clinical stage-III and over-expression of HER-2and PR protein.
3. The5years recurrence or metastasis rate had no significant correlationAIB-1protein, while the5years recurrence or metastasis rate was lower in thegroup of over-expression of PAX2protein.
方法：搜集乳腺癌术后病理证实为ER阳性，并接受他莫西芬(TAM)规范治疗患者肿瘤组织标本共88例，根据随访结果显示：5年无瘤生存（TAM治疗敏感）患者50例，5年内出现局部复发或远位转移（TAM耐药）患者38例，通过S-P法测定乳腺癌组织石蜡病理标本的PAX2和AIB-1蛋白表达水平，分析二者的量化关系，以及与复发转移率的关系，并按患者的临床病理资料：年龄、月经状况、肿瘤大小、临床分期、病理类型、组织学分级、腋淋巴结转移情况、ER、PR、HER-2等因素进行分层分析二者蛋白表达强度的差异。
运用SPSS13.0统计软件包中完全随机设计两样本率及多样本率比较的χ2检验，以α=0.05为检验水准。
结果：
1.随访结果：
88例乳腺癌患者术后5年内无瘤生存共50例；术后5年内出现局部复发或远位转移共38例，平均无病生存期（disease-free survival, DFS）45个月，平均总生存期（overall survival, OS）56个月。
2.PAX2蛋白表达强度与临床病理学特征的关系
88例乳腺癌患者按年龄分为两组（<50岁和≥50岁），经统计学分析，PAX2蛋白的高表达在不同年龄组间无统计学差异（χ~2=1.349；p=0.246），提示PAX2蛋白表达的高低与乳腺癌患者的年龄无关。
88例乳腺癌患者按月经状况分为两组（绝经前和绝经后），经统计学分析，PAX2蛋白的高表达在不同月经状况组间无统计学差异（χ~2=0.134；p=0.714），提示PAX2表达的高低与乳腺癌患者的月经状况无关。
88例乳腺癌患者按肿瘤大小分为两组（≤5cm和>5cm），经统计学分析，PAX2蛋白的高表达在不同肿瘤大小组间有统计学差异（χ~2=4.244；p=0.039），提示PAX2蛋白表达率在T>5cm组中较低。
88例乳腺癌患者按临床分期分为两组（I~II期和III期），经统计学分析，PAX2蛋白的高表达在不同临床分期组间无统计学差异（χ~2=0.243；p=0.622），提示PAX2蛋白表达的高低与乳腺癌患者的临床分期无关。
88例乳腺癌患者按病理学类型分为三组（浸润性导管癌、浸润性小叶癌和其他类型），经统计学分析，PAX2蛋白的高表达在不同病理学类型组间无统计学差异（χ~2=3.158；p=0.206），提示PAX2蛋白表达的高低与乳腺癌患者的病理类型无关。
88例乳腺癌患者按组织学分级分为两组（I~II级和III级），经统计学分析，PAX2蛋白的高表达在不同组织学分级组间无统计学差异（χ~2=0.085；p=0.771），提示PAX2表达的高低与乳腺癌患者的组织学分级无关。
88例乳腺癌患者按腋窝淋巴结转移状况分为两组（无转移，有转移），经统计学分析，PAX2蛋白的高表达在淋巴结转移状况组间无统计学差异（χ~2=0.477；p=0.490）。PAX2蛋白的高表达在淋巴结转移状况组间无统计学差异，按腋窝淋巴结转移个数分为三组（无转移，转移1~3个淋巴结和＞3个淋巴结），经统计学分析，PAX2蛋白的高表达率在淋巴结转移个数组间无统计学差异（χ~2=1.517；p=0.468），提示PAX2蛋白表达的高低与乳腺癌患者腋窝淋巴结转移无关。
88例乳腺癌患者按HER-2蛋白表达水平分为两组（低表达和高表达），经统计学分析， PAX2蛋白的高表达在不同HER-2蛋白表达水平组间有统计学差异（χ~2=5.301；p=0.021），提示PAX2蛋白在HER-2蛋白过表达乳腺癌患者中表达率较低。
88例乳腺癌患者按ER表达水平分为三组（+）、（++）和（+++），经统计学分析，PAX2蛋白的高表达在不同ER蛋白表达水平组间无统计学差异（χ~2=1.130；p=0.568），提示PAX2蛋白表达的高低与乳腺癌患者ER蛋白的表达无关。
88例乳腺癌患者按PR表达水平分为两组（阴性和阳性），经统计学分析，PAX2蛋白的高表达在不同PR表达组间无统计学差异（χ~2=0.488；p=0.485），提示PAX2蛋白表达的高低与乳腺癌患者PR蛋白的表达无关。
3．AIB-1蛋白表达与临床病理学特征的关系
88例乳腺癌组织按患者年龄分为两组（<50岁和≥50岁），经统计学分析， AIB-1蛋白的高表达在不同年龄组间无统计学差异（χ~2=0.549；p=0.459），提示AIB-1蛋白表达的高低与乳腺癌患者的年龄无关。
88例乳腺癌组织按患者月经状况分为两组（绝经前和绝经后），经统计学分析，AIB-1蛋白的高表达在不同月经状况组间无统计学差异（χ~2=0.074；p=0.785），提示AIB-1蛋白表达的高低与乳腺癌患者的月经状况无关。
88例乳腺癌组织按肿瘤直径分为两组（≤5cm和>5cm），经统计学分析，AIB-1蛋白的高表达在不同肿瘤大小组间无统计学差异（χ~2=0.433；p=0.511），考虑蛋白AIB-1蛋白表达的高低与乳腺癌患者的肿瘤大小无关。
88例乳腺癌患者按临床分期分为两组（I~II期和III期），经统计学分析，AIB-1蛋白的高表达在不同临床分期组间有统计学差异（χ~2=7.140；p=0.008），AIB-1蛋白在III期乳腺癌中表达率较高。
88例乳腺癌患者按病理学类型分为三组（浸润性导管癌、浸润性小叶癌和其他类型），经统计学分析，AIB-1蛋白的高表达在不同病理学类型组间无统计学差异（χ~2=2.214；p=0.331），提示AIB-1蛋白表达的高低与乳腺癌患者的病理类型无关。
88例乳腺癌患者按组织学分级分为两组（I~II级和III级），经统计学分析，AIB-1蛋白的高表达在不同组织学分级组间无统计学差异（χ~2=0.155；p=0.694），提示AIB-1蛋白表达的高低与乳腺癌患者的组织学分级无关。
88例乳腺癌患者按腋窝淋巴结转移状况分为两组（无转移，有转移），经统计学分析，AIB-1蛋白的高表达在淋巴结转移状况组间无统计学差异（χ~2=2.370；p=0.124）。按腋窝淋巴结转移个数分为三组（无转移，1~3个淋巴结转移和>3个淋巴结转移），经统计学分析，AIB-1蛋白的高表达在不同淋巴结转移个数组间无统计学差异（χ~2=2.399；p=0.301），提示AIB-1蛋白表达的高低与乳腺癌患者腋窝淋巴结转移无关。
88例乳腺癌患者按HER-2蛋白表达水平分为两组（低表达和高表达），经统计学分析，AIB-1蛋白的高表达在不同HER-2蛋白表达水平组间有统计学差异（χ~2=7.912；p=0.005），提示AIB-1蛋白在HER-2过表达组中表达率较高。
88例乳腺癌患者按ER蛋白表达水平分为两组（+）、（++）和（+++），经统计学分析，AIB-1蛋白的高表达在不同ER蛋白表达水平组间无统计学差异（χ~2=2.247；p=0.325），考虑AIB-1蛋白表达的高低与乳腺癌患者ER蛋白的表达无关。
88例乳腺癌患者按PR表达水平分为两组（阴性和阳性），经统计学分析，发现AIB-1蛋白的高表达在不同PR蛋白表达水平组间有统计学差异（χ~2=3.930；p=0.047），考虑AIB-1蛋白在PR蛋白阳性组中表达率较高。
4.乳腺癌复发转移状况与PAX2、AIB-1蛋白表达的关系：
88例乳腺癌患者中，经统计学分析，乳腺癌复发转移率在不同PAX2蛋白表达组中有统计学差异（χ~2=4.219；p=0.040），提示PAX2高表达患者复发转移率较低，预后较理想。
88例乳腺癌患者中，经统计学分析，复发转移率在不同AIB-1蛋白表达组中无统计学差异（χ~2=0.252；p=0.616），说明AIB-1蛋白表达水平对预后判定不敏感。
结论：
在乳腺癌术后ER阳性并接受他莫西芬(TAM)规范治疗患者中：
1. PAX2蛋白表达与乳腺癌患者年龄、月经状况、临床分期以及乳腺癌标本病理类型、组织学分级、淋巴结有无转移及转移个数、ER蛋白、PR蛋白表达水平等因素均无关，PAX2蛋白高表达在肿瘤直径T>5cm组中与HER-2蛋白过表达组中较低；
2. AIB-1蛋白表达与乳腺癌患者年龄、月经状况、肿瘤大小以及乳腺癌标本病理类型、组织学分级、淋巴结有无转移及转移个数、ER表达水平等因素均无关，AIB-1蛋白高表达在临床分期III期组、PR蛋白阳性组与HER-2蛋白过表达组中较高；
3. AIB-1蛋白表达对乳腺癌预后判定不敏感；PAX2蛋白高表达患者5年内复发转移率较低，预后较好。
Objective: In recent years, as a rising of incidence rate, breast cancer hadbecome the most important malignant tumors treated to women's health. Ithad become the most successful and effective treatment for hormonereceptor-positive breast cancer to assist endocrine therapy with representativeof tamoxifen. So in these years, the studis have foucs on the resistance oftamoxifen. Research have shown that PAX2（Paired box gene2） andAIB-1(Amplified in breast cancer-1) regulates the transcription level ofhuman epidermal growth factor receptor-2(ERBB2/Her-2) during thetreatment to estrogen receptor(ER)-postive breast cancer with tamoxifen.Further PAX2and AIB-1regulated the expression of HER-2protein, andinflunced the tamoxifen therapy of ER-positive breast cancer patients. In thisstudy, we detected the expression of PAX2and AIB-1protien of88ER-positive patients treated with tamoxifen (TAM) after modified radicalmastectomy with streptavidin peroxdase （S-P） conjugated method.Analysed the relationship between the expression levels anti-estrogentherapy resistance, and promted new indicators for the reasonable choice andvalidity determination of Endocrine therapy of breast cancer.
Methods: Collected88tumor tissue samples of ER-positive patientstreated with tamoxifen (TAM) after modified radical mastectomy.According to follow-up results within5years:50cases of patients were freesurvival (TAM sensitive), and38cases of patients appeared local recurrenceor distant metastasis (TAM-resistance). Detected the expression of PAX2andAIB-1protein of breast cancer tissues, analysed the quantitative relationshipbetween these two protein, and the correlation between the expression level ofPAX2, AIB-1and TAM treatment. In addition, contrast the difference between different groups according to a variety of factors, including age, menstrualstatus, clinical stage, diameter of the tumors, histology grade, state of themetastatic axillary lymph nodes, pathology type and the expression of ER, PR,HER-2on protein level.
All statistical analyses were performed with Chi-square test of SPSS13.0software. α=0.05was the size of the test．
Result：
1. Follow-up results:
Among88cases of breast cancer patients, there were50cases appearedtumor-free survival, while38cases appeared local recurrence or distantmetastasis within5years after surgery, with the mean disease-freesurvival(DFS) of20month and the mean overall survival(OS) of32month.
2. The relationship between the expression of PAX2protein and Clinical andpathological features.
88cases of breast cancer patients were divided into two groups accordingto the age(<50years and≥50years), the over-expression of PAX2proteinbetween them had no significant difference (χ~2=1.349, p=0.246)． Consideredthat the expression density of PAX2protein had no significant correlationbetween the age of the patients.
88cases of breast cancer patients were divided into two groups accordingto the menstrual status (premenopause and postmenopause), theover-expression of PAX2protein between them had no significant difference(χ~2=0.134, p=0.714)． Considered that the expression density of PAX2proteinhad no significant correlation between the menstrual status of the patients.
88cases of breast cancer patients were divided into two groups accordingto the diameter of the tumors (≤5cm and>5cm), the over-expression of PAX2protein between them had significant difference (χ~2=4.244,p=0.039)． Considered that the expression rate of PAX2protein was lower inthe group of T>5cm.
88cases of breast cancer patients were divided into two groups accordingto the clinical stage (stage I~II and III), the over-expression of PAX2protein between them had no significant difference (χ~2=0.243, p=0.622)． Consideredthat the expression density of PAX2protein had no significant correlationbetween the clinical stage of the patients.
88cases of breast cancer patients were divided into two groups accordingto the histological grade (grade I~II and III), the over-expression of PAX2protein between them had no significant difference (χ~2=0.085,p=0.771)． Considered that the expression density of PAX2protein had nosignificant correlation between the histological grade of the patients.
88cases of breast cancer patients were divided into two groups accordingto the state of the axillary lymph nodes (negative and positive), theover-expression of PAX2protein between them had no significant difference(χ~2=0.477, p=0.490). And we divided them into three groups according to thestate of the axillary lymph nodes (negative,1~3， and＞3), theover-expression of PAX2protein among them had no significant difference(χ~2=1.517, p=0.468)． Considered that the expression density of PAX2proteinhad no significant correlation between the state of the axillary lymph nodes ofthe patients.
88cases of breast cancer patients were divided into three groups accordingto the state of the pathological types (invasive ductal carcinoma, invasivelobular carcinoma and other), the over-expression of PAX2protein amongthem had no significant difference (χ~2=3.158, p=0.206)． Considered that theexpression density of PAX2protein had no significant correlation between thepathological types of the patients.
88cases of breast cancer patients were divided into two groups accordingto the expression level of HER-2(low-expression and over-expression), theover-expression of PAX2protein between them had significant difference(χ~2=5.301, p=0.021)． Considered that the expression level of PAX2protein islower in the group of over-expression of HER-2protien.
88cases of breast cancer patients were divided into two groups accordingto the expression level of ER (+),(++) and (+++), the over-expression ofPAX2protein between them had no significant difference (χ~2=1.130, p=0.568)． Considered that the expression density of PAX2protein had nosignificant correlation between the expression level of ER.
88cases of breast cancer patients were divided into two groups accordingto the expression level of PR (negative and positive), the over-expression ofPAX2protein between them had no significant difference (χ~2=0.488,p=0.485)． Considered that the expression density of PAX2protein had nosignificant correlation between the expression level of PR.
3. The relationship between the expression of AIB-1protein and Clinical andpathological features.
88cases of breast cancer patients were divided into two groups accordingto the age(<50years and≥50years), the over-expression of AIB-1proteinbetween them had no significant difference (χ~2=0.549, p=0.459)． Consideredthat the expression density of AIB-1protein had no significant correlationbetween the age of the patients.
88cases of breast cancer patients were divided into two groups accordingto the menstrual status (premenopause and postmenopause), theover-expression of AIB-1protein between them had no significant difference(χ~2=0.074, p=0.785)． Considered that the expression density of AIB-1proteinhad no significant correlation between the menstrual status of the patients.
88cases of breast cancer patients were divided into two groups accordingto the diameter of the tumors (≤5cm and>5cm), the over-expression of AIB-1protein between them had no significant difference (χ~2=0.433,p=0.511)． Considered that the expression density of AIB-1protein had nosignificant correlation between the diameter of the tumors of the patients..
88cases of breast cancer patients were divided into two groups accordingto the clinical stage (stage I~II and III), the over-expression of AIB-1proteinbetween them had no significant difference (χ~2=7.140, p=0.008)． Consideredthat the expression level of AIB-1protein is higher in the group of the clinicalstage III.
88cases of breast cancer patients were divided into two groups accordingto the histological grade (grade I~II and III), the over-expression of AIB-1 protein between them had no significant difference (χ~2=0.155,p=0.694)． Considered that the expression density of AIB-1protein had nosignificant correlation between the histological grade of the patients.
88cases of breast cancer patients were divided into two groups accordingto the state of the axillary lymph nodes(negative and positive), theover-expression of AIB-1protein among them had no significant difference(χ~2=2.370, p=0.124). And we divided them into three groups according to thestate of the axillary lymph nodes(negative,1~3，and>3), the over-expressionof AIB-1protein among them had no significant difference (χ~2=2.399,p=0.301)． Considered that the expression density of AIB-1protein had nosignificant correlation between the state of the axillary lymph nodes of thepatients.
88cases of breast cancer patients were divided into three groups accordingto the state of the pathological types (invasive ductal carcinoma, invasivelobular carcinoma and other), the over-expression of AIB-1protein amongthem had no significant difference (χ~2=2.214, p=0.331)． Considered that theexpression density of AIB-1protein had no significant correlation between thepathological types of the patients.
88cases of breast cancer patients were divided into two groups accordingto the expression level of HER-2(low-expression and over-expression), theover-expression of AIB-1protein between them had significant difference(χ~2=7.912, p=0.005)． Considered that the expression level of AIB-1protein islower in the group of over-expression of HER-2protein.
88cases of breast cancer patients were divided into two groups accordingto the expression level of ER (+),(++)and(+++), the over-expression of AIB-1protein between them had no significant difference (χ~2=2.247,p=0.325)． Considered that the expression density of AIB-1protein had nosignificant correlation between the expression level of ER protein.
88cases of breast cancer patients were divided into two groups accordingto the expression level of PR (negative and positive), the over-expression ofAIB-1protein between them had no significant difference (χ~2=3.930, p=0.047)． Considered that the expression level of AIB-1protein is higher inthe group of PR protein positive.
4. Relationship between PAX2protein, AIB-1protein and recurrence ormetastasis of breast cancer.
Among88cases of breast cancer,38cases appeared recurrence ormetastasis, while50cases were free survival within5years. After statisticalanalysis, recurrence or metastasis rate of breast cancer patients had nosignificant difference between different groups of expression of AIB-1protein(χ~2=0.252, p=0.616), while had significant difference between differentgroups of PAX2protein(χ~2=4.219, p=0.040). Considered that AIB-1proteinwas not sensitive for prognosis of TAM treatment, while recurrence ormetastasis rate of breast cancer patients was lower in the group ofover-expression of PAX2protein.
Conclusion：
Among88cases of the ER-positive breast cancer patients treated withtamoxifen (TAM)：
1. The expression of PAX2in the breast cancer tissues had no significantcorrelation with age, menstrual status, clinical stage, histology grade, state ofthe metastatic axillary lymph nodes, pathology type and the expression of ER,PR on protein level. The PAX2protein had lower over-expression rate in bothgroup of T>5cm and over-expression of HER-2protein.
2. The expression of AIB-1in the breast cancer tissues had no significantcorrelation with age, menstrual status, diameter of the tumors, histology grade,state of the metastatic axillary lymph nodes, pathology type and the expressionof ER protein. The AIB-1protein had higher over-expression rate in bothgroup of clinical stage-III and over-expression of HER-2and PR protein.
3. The5years recurrence or metastasis rate had no significant correlationAIB-1protein, while the5years recurrence or metastasis rate was lower in thegroup of over-expression of PAX2protein.
引文
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14霍林明，廖松林，阚秀，柳剑英.乳腺增生症及乳腺癌组织学分类.中华病理学杂志.1997;06
15Kelvin Chong, Ashok Subramanian, Anup Sharma, and Kefah Mokbel.Measuring IGF-1, ER-α and EGFR Expression Can PredictTamoxifen-resistance in ER-positive Breast Cancer. Anticancer Res.2011,Jan;31:23-32
16Nicole M, Kretzer, Milu T. A noncompetitive small molecule inhibitor ofestrogen-regulated gene expression and breast cancer cell growth thatenhances proteasome-dependent degradation of estrogen receptor-α. J.Biol. Chem.2010, Dec;285:41863-41873
17Yarden, et al. Biology of HER2and its importance in breast cancer.Oncology.2001;61:1-13
18裴劼，翟笃明.104例乳腺癌CerbB-2、P53、ER、PR的表达及临床意义.中国实验诊断学,2007;11(10):1385
19Prenzel, O.M. Fischer, S. Streit, S. Hart, A. Ullrich, et al. The epidermalgrowth factor receptor family as a central element for cellular signaltransduction and diversification. Endocrinology. Relat. Cancer.2001;8:11-31
20Nunes RA, Harris LN, et al. The HER-2extracellular domain as aprognostic and predictive factor in breast cancer. Clin Breast Cancer.2002;3(2):125-35
21李宝江，朱志华，王军业等. Ki-67、P53、VEGF和CerbB-2在乳腺癌组织中表达的相关性研究及其临床意义[J].癌症,2004,23(10):1176.
22Schmidt M, B hm D, von T, et al. The humoral immune system has a keyprognostic impact in node-negative breast cancer. Cancer Res.2008;68:5405-13
23Tanner B, Hasenclever D, Stern K, et al. ErbB-3predicts survival inovarian cancer. J Clin Oncol.2006;24:4317-23
24Line H. Moi, Marianne H. Flaageng, Sara Gandini, et a1. Expression ofsteroid receptor coactivators and HER-2/neu in normal and malignantbreast tissue in controls and tamoxifen treated tumors. Cancer Res.2010,Apr;70:1242
25Gutierrez MC, Detre S, Johnston S, et a1． Molecular changes intamoxifen-resistant breast cancer：relationship between Estrogen receptor，HER-2，and p38mitogen-activated protein kinase. J Clin Oncol.2005,23(11):2469-2476
26Taranta A, Palma A, De L, Romanzo A, Massella L, Emma F. and DelloStrologo, L. Renal-coloboma syndrome: a single nucleotide deletion in thePAX2gene at exon8is associated with a highly variable phenotype. Clin.Nephrol.2007,67:1-4
27Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression of PAX2inpapillary serous carcinoma of the ovary: immunohistochemical evidenceof fallopian tube or secondary Mullerian system origin? ModPathol,2007;20:856-863
28Dressler GR, Douglass EC. PAX2is a DNA-binding protein expressed inembryonic kidney and Wilms tumor. PNAS,1992,89:1179
29Huijian Wu, Yupeng Chen, et al. Hypomethylation-linked activation ofPAX2mediates tamoxifen-stimulated endometrial carcinogenesis. Nature.2005, Dec,15(438):981-987
30Anzick SL, Kononen J, Walker IU, et a1. AIB-1, a steroid receptorcoactivator amplified in breast and ovarian cancer. Science,1997,277:965-968
31Iwase H, Omoto Y, Toyarna T, et al. Clinical significance of AIB-1expression in human breast cancer. Breast Cancer Res Treat,2003,80(3):339-345
32Murphy LC, Simon SL, Parkes A, et a1. Altered expression of estrogenreceptor coregulators during human breast tumorigenesis. Cancer Res,2000,60:6266-6271
33Shibata A, Hayashi Y, Imai T, Funahashi H, Nakao A, Seo H. Somaticgene alteration of AIB1gene in patients with breast cancer. Endocr J,2001,48(2):199-204
34Bouras T, Southey MC, Venter D.I. Over-expression of the steroidreceptor coactivator AIB-l in breast cancer correlates with the absence ofestrogen and progesterone receptors and positivity for p53and HER-2/neu.Cancer research,2001,61:903-907
35Liao L, Kuang SQ, Yuan Y, et al. Molecular structure and biologicalfunction of the cancer amplified nuclear receptor coactivator SRC-3/AIB1.J Steroid Biochem Mol Biol.2002;83(1-5):3-14
36Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, FuquaSA, et al. Role of the estrogen receptor coactivator AIB-1(SRC-3) andHER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst2003;95:353-61
37Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al.Mechanisms of tamoxifen resistance: increased estrogenreceptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J NatlCancer Inst.2004;96:926-35
38Liu Qun, Li Ji-guang, Zheng Xin-yu, et al. Expression of CD133, PAX2,ESA, and GPR30in invasive ductal breast carcinomas. Chinese MedicalJournal.2009;122(22):2763-2769
39柳光宇，邵志敏，沈镇宙.甾体类激素受体在乳腺癌发生与发展中的变化．国外医学肿瘤学分册.2004，31(1)：52-56
40周涛,李云涛,范忠林.乳腺癌组织中AIB-1蛋白表达与临床病理指标的相关性.肿瘤防治研究.2009;36:750-753
41Bautista S,Valles H,Walker RL,et a1. In breast cancer,amplification of thesteroid receptor coactivator gene AIB-1is correlated with estrogen andprogesterone receptor positivity. Clin Cancer Res.1998;4:2925-2929
42Tove Kirkegaard, Liane M. McGlynn, et al. Amplified in breast cancer1in human epidermal growth factor receptor-positive tumors oftamoxifen-treated breast cancer patients. Clin Cancer Res,2007;13:1405-1411
43Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J,Lindahl T,Pawitan Y, Hall P, Nordgren H, et al. Genetic reclassification ofhistologic grade delineates new clinical subtypes of breast cancer. CancerRes,2006,66(21):10292-10301
44武海燕，赵文辉，张清媛，刘姝伶. PAX2、AIB-1在乳腺癌内分泌治疗中作用的临床研究[A].第十届全国乳腺癌会议、第四届上海国际乳腺癌论坛论文汇编[C];2009
45Thomas J, Hanby A, Pinder S, Ellis I, Macartney J,Clements K, et al.Implications of inconsistent measurement of ER status in non-invasivebreast cancer: a study of1,684cases from the Sloane Project. Breast J.2008;14:33-8
46Euphemia Leung, Nagarajan Kannan, Geoffrey W, Krissansen, et al.MCF-7breast cancer cells selected for tamoxifen resistance acquire newphenotypes differing in DNA content, phospho-HER2and PAX2expression, and rapamycin sensitivity. Cancer Biology&Therapy.2010,May1(99):717-724
47Osborne CK, Bardou V, Hopp TA, et a1. Role of the estrogen receptorcoactivator AIB-1(SRC-3) and HER-2/neu in Tamoxifen resistance inbreast cancer. Joumal of the National Cancer Institute,2003,95:353-361
48Shou J, Massarweh S, Osborne C K, et a1. Mechanisms of tamoxifenresistance: increased estrogen receptor-HER2/neu cross-talk inER/HER2-positive breast cancer[J]. J Natl Cancer Inst.2004,96(12):926-935
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28Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, Lindahl T,Pawitan Y, Hall P, Nordgren H, et al. Genetic reclassification ofhistologic grade delineates new clinical subtypes of breast cancer. CancerRes,2006,66(21):10292-10301.
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40Euphemia Leung, Nagarajan Kannan, Geoffrey W, Krissansen, et al.MCF-7breast cancer cells selected for tamoxifen resistance acquire newphenotypes differing in DNA content, phospho-HER2and PAX2expression, and rapamycin sensitivity. Cancer Biology&Therapy,2010,May1(99),717-724
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2Aisling M, Redmond, Fiona T. Bane, et al. Coassociation of EstrogenReceptor and p160Proteins Predicts Resistance to Endocrine Treatment;SRC-1is an Independent Predictorof Breast Cancer Recurrence. ClinCancer Res.2009;15(6):2098
3Khoubehi, B, et al. Expression of the developmental and oncogenic PAX2gene in human prostate cancer. J. Urol.2006Jun;168(2):2115-2120
4Muratovska A, Zhou C, He S, Goodyer P,&Eccles MR. Paired-box genesare frequently expressed in cancer and often required for cancer cellsurvival. Oncogene.2003;22:7989-7997
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11Tove Kirkegard, Liane M. McGlynn, et al. Amplified in breast cancer-1inhuman epidermal growth factor receptor-positive tumors oftamoxifen-treated breast cancer patients. Clin Cancer Res.2007;13:1405-1411
12Annette Lebeau, Andreas Turzynski, et al. Reliability of Human EpidermalGrowth Factor Receptor2Immunohistochemistry in Breast Core NeedleBiopsies. J. Clin. Oncol.2010, July;28:3264-3270
13薛卫成,阚秀,介绍乳腺癌TNM分期系统.诊断病理学.2008;15(3):161-164
14霍林明，廖松林，阚秀，柳剑英.乳腺增生症及乳腺癌组织学分类.中华病理学杂志.1997;06
15Kelvin Chong, Ashok Subramanian, Anup Sharma, and Kefah Mokbel.Measuring IGF-1, ER-α and EGFR Expression Can PredictTamoxifen-resistance in ER-positive Breast Cancer. Anticancer Res.2011,Jan;31:23-32
16Nicole M, Kretzer, Milu T. A noncompetitive small molecule inhibitor ofestrogen-regulated gene expression and breast cancer cell growth thatenhances proteasome-dependent degradation of estrogen receptor-α. J.Biol. Chem.2010, Dec;285:41863-41873
17Yarden, et al. Biology of HER2and its importance in breast cancer.Oncology.2001;61:1-13
18裴劼，翟笃明.104例乳腺癌CerbB-2、P53、ER、PR的表达及临床意义.中国实验诊断学,2007;11(10):1385
19Prenzel, O.M. Fischer, S. Streit, S. Hart, A. Ullrich, et al. The epidermalgrowth factor receptor family as a central element for cellular signaltransduction and diversification. Endocrinology. Relat. Cancer.2001;8:11-31
20Nunes RA, Harris LN, et al. The HER-2extracellular domain as aprognostic and predictive factor in breast cancer. Clin Breast Cancer.2002;3(2):125-35
21李宝江，朱志华，王军业等. Ki-67、P53、VEGF和CerbB-2在乳腺癌组织中表达的相关性研究及其临床意义[J].癌症,2004,23(10):1176.
22Schmidt M, B hm D, von T, et al. The humoral immune system has a keyprognostic impact in node-negative breast cancer. Cancer Res.2008;68:5405-13
23Tanner B, Hasenclever D, Stern K, et al. ErbB-3predicts survival inovarian cancer. J Clin Oncol.2006;24:4317-23
24Line H. Moi, Marianne H. Flaageng, Sara Gandini, et a1. Expression ofsteroid receptor coactivators and HER-2/neu in normal and malignantbreast tissue in controls and tamoxifen treated tumors. Cancer Res.2010,Apr;70:1242
25Gutierrez MC, Detre S, Johnston S, et a1． Molecular changes intamoxifen-resistant breast cancer：relationship between Estrogen receptor，HER-2，and p38mitogen-activated protein kinase. J Clin Oncol.2005,23(11):2469-2476
26Taranta A, Palma A, De L, Romanzo A, Massella L, Emma F. and DelloStrologo, L. Renal-coloboma syndrome: a single nucleotide deletion in thePAX2gene at exon8is associated with a highly variable phenotype. Clin.Nephrol.2007,67:1-4
27Tong GX, Chiriboga L, Hamele-Bena D, et al. Expression of PAX2inpapillary serous carcinoma of the ovary: immunohistochemical evidenceof fallopian tube or secondary Mullerian system origin? ModPathol,2007;20:856-863
28Dressler GR, Douglass EC. PAX2is a DNA-binding protein expressed inembryonic kidney and Wilms tumor. PNAS,1992,89:1179
29Huijian Wu, Yupeng Chen, et al. Hypomethylation-linked activation ofPAX2mediates tamoxifen-stimulated endometrial carcinogenesis. Nature.2005, Dec,15(438):981-987
30Anzick SL, Kononen J, Walker IU, et a1. AIB-1, a steroid receptorcoactivator amplified in breast and ovarian cancer. Science,1997,277:965-968
31Iwase H, Omoto Y, Toyarna T, et al. Clinical significance of AIB-1expression in human breast cancer. Breast Cancer Res Treat,2003,80(3):339-345
32Murphy LC, Simon SL, Parkes A, et a1. Altered expression of estrogenreceptor coregulators during human breast tumorigenesis. Cancer Res,2000,60:6266-6271
33Shibata A, Hayashi Y, Imai T, Funahashi H, Nakao A, Seo H. Somaticgene alteration of AIB1gene in patients with breast cancer. Endocr J,2001,48(2):199-204
34Bouras T, Southey MC, Venter D.I. Over-expression of the steroidreceptor coactivator AIB-l in breast cancer correlates with the absence ofestrogen and progesterone receptors and positivity for p53and HER-2/neu.Cancer research,2001,61:903-907
35Liao L, Kuang SQ, Yuan Y, et al. Molecular structure and biologicalfunction of the cancer amplified nuclear receptor coactivator SRC-3/AIB1.J Steroid Biochem Mol Biol.2002;83(1-5):3-14
36Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, FuquaSA, et al. Role of the estrogen receptor coactivator AIB-1(SRC-3) andHER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst2003;95:353-61
37Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, et al.Mechanisms of tamoxifen resistance: increased estrogenreceptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J NatlCancer Inst.2004;96:926-35
38Liu Qun, Li Ji-guang, Zheng Xin-yu, et al. Expression of CD133, PAX2,ESA, and GPR30in invasive ductal breast carcinomas. Chinese MedicalJournal.2009;122(22):2763-2769
39柳光宇，邵志敏，沈镇宙.甾体类激素受体在乳腺癌发生与发展中的变化．国外医学肿瘤学分册.2004，31(1)：52-56
40周涛,李云涛,范忠林.乳腺癌组织中AIB-1蛋白表达与临床病理指标的相关性.肿瘤防治研究.2009;36:750-753
41Bautista S,Valles H,Walker RL,et a1. In breast cancer,amplification of thesteroid receptor coactivator gene AIB-1is correlated with estrogen andprogesterone receptor positivity. Clin Cancer Res.1998;4:2925-2929
42Tove Kirkegaard, Liane M. McGlynn, et al. Amplified in breast cancer1in human epidermal growth factor receptor-positive tumors oftamoxifen-treated breast cancer patients. Clin Cancer Res,2007;13:1405-1411
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44武海燕，赵文辉，张清媛，刘姝伶. PAX2、AIB-1在乳腺癌内分泌治疗中作用的临床研究[A].第十届全国乳腺癌会议、第四届上海国际乳腺癌论坛论文汇编[C];2009
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