The expression of Fhit protein is related inversely to disease progression in patients with breast carcinoma

BACKGROUND: The FHIT gene, located at human chromosome 3p14.2, frequently is deleted in a number of human tumors, including breast carcinoma. Its protein product (Fhit) is presumed to have tumor suppressor function. Loss of expression of a tumor suppressor gene is an important step in tumor progression from premalignant, to in situ, to invasive carcinoma. METHODS: In the current study, Fhit expression was examined in invasive carcinomas and in epithelial lesions representing stages of carcinoma progression in 50 mastectomy specimens using immunohistochemical methods. RESULTS: Normal ductal and lobular epithelium consistently and strongly expressed Fhit. A complete loss of or a significant reduction in Fhit expression was observed in 72% of breast carcinomas. A statistically significant, negative correlation in Fhit expression among the stages of disease progression in Fhit negative breast carcinomas was observed (normal epithelium > hyperplasia > atypical hyperplasia and carcinoma in situ > invasive carcinoma), whereas no loss of Fhit expression in precursor lesions was observed in Fhit positive tumors. CONCLUSIONS: These observations are consistent with the observed role of FHIT as a tumor suppressor gene in the pathogenesis of specific subsets of carcinomas.     

端粒酶hTERT mRNA表达在乳腺癌进展中的意义及其与p53的相关性

目的 探讨端粒酶hTERT mRNA表达在人乳腺癌发生、发展中的意义,观察肿瘤抑制基因p53与hTERT mRNA表达的关系。方法 收集浸润性导管癌标本25例,导管原位癌标本18例,导管上皮不典型增生标本20例,导管上皮单纯性增生标本7例,癌旁正常乳腺组织标本12例。用原位杂交法检测hTERT mRNA表达,并用免疫组化方法检测乳腺导管癌的p53蛋白表达。结果 hTERT mRNA在癌旁正常乳腺组织、乳腺导管单纯性增生中未见表达;在导管不典型增生、导管原位癌、浸润性导管癌中的阳性率分别为25．0％、83．3％和88．0％。导管原位癌、浸润性导管癌组织hTERT mRNA表达明显高于癌旁正常乳腺组织、乳腺导管单纯性增生和导管不典型增生组织（P〈0．05）。hTERT mRNA表达与浸润性导管癌肿块大小及淋巴结转移与否无关（P〉0．05）。43例乳腺导管癌中,hTERT mRNA表达与p53蛋白表达呈正相关（r=0．5540,P〈0．01）。结论 端粒酶hTERT mRNA表达可能在乳腺导管癌的组织发生中起关键作用,半定量原位检测hTERT mRNA表达,可为导管上皮不典型增生与导管原位癌的鉴别诊断提供帮助。p53突变可能与乳腺导管癌hTERT基因转 录激活有关。     

bcl-2蛋白在良性乳腺病变及乳腺癌组织中的表达

目的　观察bcl-2蛋白在乳腺癌及良性乳腺病变中的表达。方法　采用免疫组化方法检测 15例正常乳腺组织、18例导管增生、10例不典型导管增生 ,10例小叶增生 ,6 9例浸润型乳腺癌和 45例乳腺导管原位癌中bcl -2蛋白表达。结果　bcl -2在 15例正常乳腺组织、18例导管增生、10例不典型导管增生及 10例小叶增生中均呈阳性 (10 0 % ) ,且均为高表达 ;bcl -2蛋白在 6 9例浸润型乳腺癌和 45例导管原位癌的表达阳性率分别为 6 5 2 % (45例 )和 75 6 % (3 4例 )。结论　bcl -2蛋白在正常乳腺组织良性乳腺病变的表达明显高于乳腺癌的表达。可能是在肿瘤的发展过程中bcl -2失去表达的结果 ,其原因和机理还有待进一步研究     

iNOS在不同乳腺病理组织中的表达水平及其与肿瘤临床预后的相关性

目的:检测诱导型一氧化氮合酶（iNOS）在正常乳腺组织、不典型增生、原位癌以及浸润性乳腺癌组织中的表达水平,探讨其与浸润性乳腺癌临床相关病理指标及临床预后相关性。方法:收集148例不同乳腺病理组织（28例不典型增生、40例导管内癌及80例浸润性乳腺癌）以及20例正常乳腺组织,使用免疫组化SP法检测各组中iNOS的表达水平。分析浸润性乳腺癌中iNOS表达水平与肿瘤大小、腋窝淋巴结受累情况、TNM分期等临床病理指标,以及与临床预后的相关性。结果:iNOS在乳腺正常组织中未见阳性表达;而在乳腺不典型增生组织、原位癌组织及浸润性乳腺癌组织中阳性率分别为25.0%、52.5%及78.8%,各组间差异有统计学意义（均P<0.05）。在浸润性乳腺癌中,随着临床分期越晚及肿瘤直径越大,iNOS染色阳性率逐渐升高。在原位癌中iNOS染色阳性组5年无病生存率（61.9%）低于阴性组（84.2%）,差异有统计学意义（P<0.05）;而在浸润性乳腺癌中,iNOS染色阳性组5年无病生存率（63.5%）与阴性组（70.6%）无统计学差异（P>0.05）。结论:iNOS在乳腺癌发生的早期阶段（不典型增生）即已出现表达升高,其表达水平与临床分期与肿瘤直径相关,并影响原位癌患者预后。因此,iNOS可作为乳腺癌早期诊断及预后评估的潜在指标。     

Regulation of in situ to invasive breast carcinoma transition

The transition of ductal carcinoma in situ (DCIS) to invasive carcinoma is a poorly understood key event in breast tumor progression. Here, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a model of human DCIS and primary breast tumors. Progression to invasion was promoted by fibroblasts and inhibited by normal myoepithelial cells. Molecular profiles of isolated luminal epithelial and myoepithelial cells identified an intricate interaction network involving TGFbeta, Hedgehog, cell adhesion, and p63 required for myoepithelial cell differentiation, the elimination of which resulted in loss of myoepithelial cells and progression to invasion.     

Ductal carcinoma<Emphasis Type="Italic">in situ</Emphasis> and related lesions of the breast: Recent advances in pathology practice

The incidence of ductal carcinoma in situ (DCIS) of the breast has increased significantly in Japanese women. It comprises 14.1% (172/1216) of all primary breast cancers at our institute, and nowadays this histological type is familiar to the surgeons and pathologists of any institute. Several subclassifications have been published recently. Most based on nuclear atypia and the presence of comedonecrosis, and sometimes on the structures of the involved glands. These classifications are correlated with the biological behavior, tumor extent and the risk for local recurrences. The diagnostic accuracy of minimally invasive procedures (aspiration biopsy cytology/core needle biopsy) may differ between subclasses. Atypical ductal hyperplasia (ADH) and microinvasive ductal carcinomas are lesions which resemble but deviate from the DCIS spectrum. The incidence of ADH seems to be lower than in Western countries. Patients with ADH may have a risk for subsequent breast cancer, because ADH is frequently associated with contralateral breast carcinomas. Microinvasion should be treated with caution, but we could not find any metastatic foci in microinvasive ductal carcinomas (T1mic). Tentatively, ADH may be treated similarly to non-comedo (low-grade) DCIS cases, according to our limited clinical experience.     

Expression of HIF-1α in breast cancer and precancerous lesions and the relationship to clinicopathological features简

Objective： The aim of this study was to observe the expressions and clinical significance of HIF-1a in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： We analyzed the HIF-1a expression in 128 cases of invasive ductal carcinomas, 146 precancerous lesions patients including 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia. 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The specimens were evaluated for HIF-1a, estrogen receptor （ER） ＆ progesterone receptor （PR）, epidermal growth factor receptor type 2 （HER2/neu） and Ki-67. Immunoreactivity was semi-quantitatively evaluated in at least 1000 cells examined under the microscope at 40 x magnification and recorded as the percentage of positive tumor cells over the total number of cells examined in the same area. The percentage scores were subsequently categorized. The express of HIF-1a and their relationship with multiple biological parameters including ER ＆ PR, HER2/neu and Ki-67, the biomarkers levels of CA153, CA125 TSGF, and CEA in blood serum and nipple discharge, histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： Compared with usual ductal hyperplasia, the positive expression rate of HIF-1a in atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinomas group was significantly increased （P 〈 0.01）. The positive rates of HIF-1a in invasive ductal carcinomas were 68.75%, which were significantly higher than that in ductal carcinoma in situ （43.8%）, atypical ductal hyperplasia （31.6%）, usual ductal hyperplasia （9.4%; X2 = 13.44, 22.27, 52.79, respectively, P 〈 0.01）. Statistical analysis showed that difference of abnormal expression rate of HIF-1a between ductal carcinoma in situ and usual ductal hyperplasia （X2 = 18.37, P = 0.00）, atypical ductal hyperplasia and usual ductal hyperplasia （x2 = 8.14, P = 0.00） was significant （P = 0.00）. However, no significant difference in the positive expression rate of HIF-1a was found between atypical ductal hyperplasia and ductal carcinoma in situ tissue （X2 = 2.19, P = 0.14）. There was a significantly difference in the mean HIF-1a frequency between ER ＆ PR positive invasive ductal carcinomas group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was not difference in the mean HIF-1a between age （〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm; P 〉 0.05）. The nipple discharge and serum levels of CA153, TSGF, CA125 and CEA in invasive ductal carcinomas HIF-1a positive patients were significantly higher than those in the negative patients （P 〈 0.05）. Conclusion： In breast cancer, HIF-1a expressibn was abnormally increased. The aberration of HIF-1a may play a key role during oncogenesis （atypical ductal hyperplasia or ductal carcinoma in situ） and promote breast cellular transformation into malignancy, a finding useful for further understanding of tumorigenesis. The abnormal expression of HIF-1a may be as an early event in the development of breast tumor. The over-expression of HIF-1a might be important biological markers for invasion, metastasis and recurrence of breast cancer.     

THE EXPRESSION OF APOPTOSIS RELATED GENES IN THE PROCESS OF CANCERATION OF ATYPICAL HYPERPLASIA OF MAMMARY DUCT

Objective： To investigate the expression of apoptosis related genes p53 and bcl-2 in atypical hyperplasia of mammary duct and the relationship between the gene expression and oncogenesis of breast. Methods： mRNA of apoptosis related gene p53 and bcl-2 were detected by in situ hybridization in 44 cases of atypical ductal hyperplasia. p53 protein expression was detected by immunohistochemistry. The data were compared with those of 6 cases of benign hyperplasia and 26 cases of breast carcinoma. Results： The expression of p53 mRNA was 66.7% in benign hyperplasia, 40% in atypical ductal hyperplasia （55.6% in mild, 41.7% in medium, 26.1% in severe） and 19.2% in carcinoma （of which 21.4% were intraductal carcinoma and 16.7% were invasive）. The expression of p53 protein was negative in benign hyperplasia, 24% in atypical hyperplasia （mild 11.1%, medium 25%, severe 34.8%）, 38.5% in carcinoma （intraductal carcinoma 35.7%, invasive ductal carcinoma 41.7%）. The expression of bcl-2 was negative in benign hyperplasia, 78.6% in intraductal carcinoma, 83.3% in invasive ductal carcinoma. Conclusion： Loss and mutation of p53 gene and excessive expression bcl-2 mRNA were detected in severe atypical ductal hyperplasia.     

Analysis of normal epithelial cell specific-1 (NES1)/kallikrein 10 mRNA expression by in situ hybridization, a novel marker for breast cancer.

PURPOSE: Normal epithelial cell specific-1 (NES1)/kallikrein 10 gene is expressed in normal mammary and prostate epithelial cells, but the expression of NES1 mRNA and protein is markedly reduced in established breast and prostate cancer cell lines although the NES1 gene is intact. Here, we wished to assess whether NES1 expression is down-regulated in primary breast cancers. EXPERIMENTAL DESIGN: We developed and used an in situ hybridization technique with an antisense NES1 probe to detect NES1 mRNA in sections of normal breast specimens, typical and atypical ductal hyperplasia, ductal carcinoma in situ, and infiltrating ductal carcinoma. RESULTS: All of the 30 normal breast specimens showed high NES1 expression. Notably, 18 (75%) of 24 typical and atypical breast hyperplasia specimens showed high NES1 expression, with weak-to-moderate expression in 6 (25%). Significantly, 13 (46%) of 28 ductal carcinoma in situ specimens lacked NES1 expression, and the remaining 15 (54%) showed weak-to-moderate expression. Finally, 29 of 30 (97%) infiltrating ductal carcinoma grades I-III samples lacked NES1 mRNA, with weak expression in the remaining one sample. CONCLUSIONS: Our results demonstrate that NES1 mRNA is expressed in normal breast tissue and benign lesions, with loss of NES1 expression during tumor progression. We suggest that NES1 expression may serve as a molecular tool in the study of breast cancer progression. Studies with larger series of specimens should help assess whether NES1 expression can be a diagnostic and/or prognostic marker in breast and other cancers.     

Expression and clinical significance of E-cadherin, β-catenin and E-cadherin-catenins complex in breast cancer and precancerous lesions简

Objective： The aim of our study was to observe the expressions and clinical Significance of E-cadherin, β-catenin and E-cadherin-catenins complex in breast cancer and precancerous lesions, and analyze the relationship between the expressions and clinicopathological features in breast cancer. Methods： Immunhistochemical UltraSensitiveTM S-P method was employed to detect the expression of E-cadherin, β-catenin and E-cadherin-catenins complex in 128 cases of invasive ductal carcinomas, 89 cases of ductal carcinoma in situ and 57 cases of atypical ductal hyperplasia, 53 cases of usual ductal hyperplasia breast tissues were selected as a control group. The express of E-cadherin, β-catenin and their relationship with mult biological parameters including histological grade, region lymph node metastasis, distant metastasis and recurrence on files were also assessed. Results： （1） The staining patterns character of E-cadherin, β-catenin and E-cadherin-catenins complex： In UDH breast tissues, E-cadherin and a-catenin were expressed on cell membrane of ductal and acinic cells, showing cellular contour and border among cells. The abnormal expression of the three proteins occurred in breast invasive ductal carcinomas, ductal carcinoma in situ and atypical ductal hyperplasia tissues, showing cytoplasmic or nuclear staining, decrease and loss of cytomembrane staining. （2） The abnormal expression rates of E-cadherin, β-catenin and E-cadherin-catenins complex in invasive ductal carcinomas were 53.91%, 65.63% and 81.25%, which were significantly higher than that in ductal carcinoma in situ, atypical ductal hyperplasia, usual ductal hyperplasia tissues （P 〈 0.01）. Compared with usual ductal hyperplasia breast tissues group, the abnormal expression rates of E-cadherin, β-catenin and E-cadherin-catenins complex were significantly decreased （P 〈 0.01） in the breast cancer group. However, there was no significance of the abnormal expression rate between ductal carcinoma in situ and atypical ductal hyperplasia tissues groups （X2 = 0.76, P = 0.38; x2 = 0.14, P = 0.70; x2 = 0.81, P = 0.37; X2 = 2.19, P = 0.14） （P 〉 0.05）. （3） There was a significantly difference in the mean E-cadherin, β-catenin and E- cadherin-catenins complex frequency between estrogen receptor ＆ progesterone receptor positive IDC group and negative group, epidermal growth factor receptor type 2 （HER2/neu） positive and negative groups, Ki-67 proliferation index 〈 14% and 〉 14% groups, histological grade （I ＋ II） and grade III invasive ductal carcinomas groups, with lymph node metastasis, distant metastasis and recurrence groups （P 〈 0.05） and without groups （P 〈 0.05）. However, there was no difference in the mean E-cadherin, β-catenin and E-cadherin-catenins complex frequency between age （_〈 50 years vs 〉 50 years）, tumor diameter （〈 2 cm vs 〉 2 cm） （P 〉 0.05）. Conclusion： In breast cancer, the expressions of E-cadherin, β-catenin and E-cadherin-catenins complex are abnormally decreased and are correlated with pathology grade, differentiation disturbance and metastasis. E- cadherin and β-catenin may be as the predictors for prognosis. Combined detection may improve accuracy and sensitivity of predicting metastasis and prognosis of breast Cancer.     

乳腺癌组织中HIF-1α的表达水平及其与肿瘤血管生成相关性研究

目的:探讨缺氧诱导因子1α（hypoxia inducible factor 1α,HIF-1α）在乳腺正常组织、不典型增生、原位癌、浸润性癌组织中的表达水平,分析其与浸润性乳腺癌临床病理指标及肿瘤血管生成之间的关系。方法:收集20例正常乳腺组织、23例不典型增生、34例原位癌、80例浸润性乳腺癌组织标本,用免疫组化SP法检测各组中HIF-1α的表达,分析其在浸润性乳腺癌中的表达与肿瘤大小、腋窝淋巴结受累情况、TNM分期、组织学分级、激素受体等临床病理指标之间的关系。并用CD34标记肿瘤新生血管,分析HIF-1α表达对肿瘤血管生成的影响。结果:HIF-1α在正常乳腺组织中未见阳性表达,在乳腺不典型增生组织、原位癌组织、浸润性癌组织中表达阳性率分别为8.7%（2/23）、47.1%（16/34）及73.8%（59/80）,表达率依次增高,乳腺原位癌组织与不典型增生组织之间、乳腺浸润癌组织与原位癌组织之间差异具有统计学意义（P＜0.01）。在浸润性乳腺癌中,HIF-1α的表达在不同肿瘤直径、组织学分级及淋巴结转移分组中差异具有统计学意义（P均＜0.05）。浸润性导管癌HIF-1α阳性组MVD值（11.74±4.398）明显高于HIF-1α表达阴性组（9.093±2.856）,差异有统计学意义（P＜0.05）。HIF-1α表达与MVD值呈正相关性（r=0.633,P＜0.05）。结论:HIF-1α在浸润性乳腺癌组织中表达水平升高,其表达上调与乳腺癌新生血管生成密切相关。     

Preferential nuclear and cytoplasmic NY-BR-1 protein expression in primary breast cancer and lymph node metastases.

PURPOSE: NY-BR-1 is a recently isolated differentiation antigen, which is expressed in normal mammary tissue and in breast cancer. However, current data are based on RT-PCR analysis and nothing is known about the presence of NY-BR-1 on a protein level. We previously generated a monoclonal antibody to NY-BR-1 to study the protein expression of NY-BR-1. METHODS: In our immunohistochemical study, NY-BR-1 was analyzed in normal tissues, various tumor types, 124 primary breast cancers, and 37 paired lymph node metastases. RESULTS: Among normal tissues, NY-BR-1 was present solely in ductal epithelium of the breast. In tumors, carcinoma in situ and invasive carcinoma of the breast were NY-BR-1 positive whereas other tumors and normal tissues were negative. Sixty percent of invasive breast carcinomas were NY-BR-1 positive, displaying cytoplasmic and/or nuclear immunoreactivity. This coexpression was verified by confocal microscopy. Although the monoclonal antibody identified intratumoral heterogeneity, a majority (72%) of NY-BR-1-positive carcinomas revealed immunoreactivity in >50% of the tumor cells. NY-BR-1 expression was more frequent in estrogen receptor-positive and lymph node-negative primary carcinomas (P < 0.05 each) and was more common in grade 1 (77%) than in grade 2 (63%) or grade 3 (50%) carcinomas (P < 0.05). This suggests that NY-BR-1 expression is lost with tumor progression. Forty-nine percent of lymph node metastases were NY-BR-1 positive. CONCLUSION: This study supports the notion that NY-BR-1 is a differentiation antigen of the breast, which is present in normal and tumorous mammary epithelium. The organ-specific expression of NY-BR-1 and its high prevalence in metastases indicate that it could be a valuable target for cancer immunotherapy.     

Immunohistochemical demonstration of metallothionein in normal human breast tissue and benign and malignant breast lesions

Metallothioneins (MTs) are a set of low molecular weight proteins with a high binding affinity to metal ions. MT over-expression has been recently demonstrated in invasive ductal carcinoma of the breast with poor clinical prognosis. In the present study, MTs have been immunohistochemically investigated in normal human breast tissue and a variety of benign, pre-invasive, and malignant breast lesions. In normal breast tissue, MTs were present in myoepithelial cells whereas the vast majority of luminal cells were MT negative. In lesions without increased cancer risk (adenosis and scleradenosis), MT was only immunolocalized in myoepithelial cells. In papillomas, MT was also found exclusively in myoepithelial cells. In most cases of epitheliosis, both the luminal and myoepithelial cells expressed MT. Atypicallobular hyperplasia, lobular carcinomain situ, and 13/15 invasive lobular carcinomas showed no MT over-expression. The two invasive lobular carcinomas with MT over-expression were classified as pleomorphic lobular carcinomas with apocrine differentiation. In contrast to lobular cancerization, 12/24 ductalin situ carcinomas and 9/20 invasive ductal carcinomas showed MT over-expression.In situ components found within invasive ductal carcinomas usually reflected the MT status of their invasive counterpart. It is concluded from our immunohistochemical results that breast carcinoma cases with MT overexpression arise from lesions which also show MT overexpression. Thus MT expression in carcinomas may be regarded as a genuine feature of the tumour cells and seems not to be related to endogenous or exogenous factors known to induce MT synthesis.     

A role for endothelin-2 and its receptors in breast tumor cell invasion

We have studied the role of endothelins (ET-1, ET-2 and ET-3) and ET receptors (ET-RA and ET-RB) in the invasive capacity of breast tumor cells, which express ET-1 and ET-2 as well as ET-RA and ET-RB. Of five human breast tumor cell lines tested, all expressed mRNAs for ET-1, ET-2, and ET-RB. ET-RA mRNA was expressed by four of five tumor cell lines. Breast tumor cells migrated toward ET-1 and ET-2 but not toward ET-3. Chemotaxis involved signaling via both receptors, and a pertussis toxin-sensitive p42/p44 mitogen-activated protein kinase (MAPK)-mediated pathway that could be inhibited by MAPK kinase (MEK)1/2 antagonists. Chemotaxis toward ETs did not involve p38 or stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) and was not inhibited by hypoxia. Incubation of tumor cells with ET-2 also increased chemotaxis toward the chemokines CXCL12 and CCL21. As well as inducing chemotaxis of tumor cells, ET-1 and ET-2 increased tumor cell invasion through Matrigel. Furthermore, stimulation of macrophage/tumor cell cocultures with ETs led to increased matrix metalloproteinase (MMP)-2 and -9 production by macrophages and a marked increase in invasion of tumor cells. Antagonism of either ET-RA or ET-RB decreased the invasion seen in ET-stimulated cocultures, as did a broad-spectrum MMP inhibitor. Immunohistochemical staining of human breast tumor sections showed increased ET and ET receptor protein expression by tumor cells in invasive ductal carcinoma compared with normal breast tissue or ductal carcinoma in situ. Furthermore, tumor cell ET and receptor expression was stronger at the invasive margin of invasive ductal carcinomas, in the lymphovascular space, and in lymph node metastases. ET expression often colocalized with ET-RB expression in all neoplastic tissue indicating a possible autocrine action of ETs. We suggest that expression of ETs and their receptors by human breast tumors, particularly in conjunction with a high macrophage infiltrate, may have a role in the progression of breast cancer and the invasion of tumor cells.     

Expression of bax and p53 proteins in the tumorigenesis and progression of breast carcinomas.

OBJECTIVES: Dysregulation of normal programmed cell death mechanisms plays an important role in the pathogenesis of breast cancer. The purpose of this study was to investigate the role of bax and p53 expression in tumorigenesis and progression of breast carcinoma as well as their relationship with proliferative and apoptotic activity. METHODS: We used immunohistochemical methods and in situ detection of apoptotic cells to examine 30 carcinomas in situ (CIS), 131 invasive breast carcinomas and 45 lymph node metastases. RESULTS: In 25% (33 of 131) of invasive breast carcinomas examined, bax expression was absent, while p53 accumulation was present in 37% (49 of 131). Interestingly, p53 accumulation and loss of bax expression occur in breast CIS as frequently as in invasive breast carcinoma. Thus, in 17% (5 of 30) of CIS bax expression was absent, and 30% (9 of 30) presented nuclear expression of p53. p53 accumulation was related to apoptosis and proliferative activity. However, the protein level of bax was unrelated to all parameters studied, including proliferation and apoptosis of tumor cells. A multivariate analysis of disease-free survival demonstrated that p53 accumulation and bax expression are not significant independent indicators of prognosis in operable breast carcinoma. Our results also show that the proportion of bax- and p53-positive cells does not vary between primary and metastatic tumors. CONCLUSIONS: p53 accumulation and loss of bax expression influence the acquisition of a malignant phenotype but seem to have no further impact on tumor progression.     

Mucin expression in mucinous carcinoma and other invasive carcinomas of the breast.

To investigate mucin expression in breast cancer, immunohistochemical staining was performed on 30 mucinous carcinomas and 95 non-mucinous invasive carcinomas. MUC2 expression was detected in all mucinous carcinomas, but only in 11.1% of invasive ductal carcinomas, and in none of the invasive lobular carcinomas and medullary carcinomas. MUC1 is often expressed in invasive breast carcinoma, but not in medullary carcinoma. Strong cytoplasmic staining was seen in invasive ductal carcinoma, in contrast to surface membrane staining in mucinous carcinoma and intracytoplasmic vacuole staining in invasive lobular carcinoma. CA19-9 and CA50 expression in more than 25% of tumor cells was seen in 17.2 and 16.0% of invasive ductal carcinomas, respectively, but not in mucinous carcinomas. CA125 and human gastric mucin were rarely expressed in breast cancer, irrespective of histologic type.     

CD133+细胞在乳腺良恶性病变中的分布特点及其临床病理意义

研究CD133+细胞在乳腺普通型增生、乳腺不典型增生、乳腺原位癌、浸润性乳腺癌中的分布特点及其与乳腺癌临床病理特征的关系。方法:采用免疫组织化学方法对45例正常乳腺组织、41例普通型增生乳腺组织、39例不典型增生乳腺组织、51例乳腺原位癌组织、121例乳腺癌组织中CD133+的表达进行检测,分析CD133+细胞在乳腺良恶性病变中的分布特点。结果:CD133+在正常乳腺组织中不表达,在乳腺普通型增生、不典型增生、原位癌、浸润性癌的表达率逐渐增高,分别为31.7%（13/41）、48.7%（19/39）、64.7%（33/51）、74.4%（90/121）,有显著性差异（P<0.01）。CD133+的表达率随乳腺癌组织学分级［Ⅰ级63.6%（21/33）、Ⅱ级72.2%（26/36）、Ⅲ级82.7%（43/52）,P<0.05］和TNM分期［Ⅰ期57.1%（12/21）、Ⅱ期69.4%（34/49）、Ⅲ期68.7%（11/16）、Ⅳ期94.3%（33/35）,P<0.001］的增高而增高;有淋巴结转移或远处转移者分别高于无转移者、无远处转移者（P<0.05）;有复发者高于无复发者（P<0.05）;与患者年龄、月经状态、肿瘤的组织学类型、肿瘤大小、ER、PR、Her-2的表达无显著相关（P>0.05）。结论:CD133+细胞可能在乳腺增生与癌变过程中起重要作用;CD133+的乳腺癌细胞与乳腺癌的侵袭、转移和复发密切相关,CD133+是提示乳腺癌恶性程度和预后的指标之一。      

p53 Protein Accumulation in Non-Invasive Lesions Surrounding p53 Mutation Positive Invasive Breast Cancers

p53 mutation is a common event in sporadic breast cancer being found in 15–50% of invasive carcinomas. The purpose of this study was to determine the earliest histologic stage at which p53 mutation could be detected with a widely used anti-p53 antibody (DO7, Novocastra) which recognizes both wild type and mutant forms. p53 expression was assessed immunohistochemically in 12 primary breast carcinomas with known p53 mutations and in all pre-malignant epithelial lesions surrounding these invasive cancers. Strong p53 nuclear staining was found in all of the tumors known to have missense mutations and none of the tumors with truncation mutations. In cases with intense staining in the invasive carcinoma, a similar quality of staining was also seen in all areas of DCIS (ductal carcinoma in situ) and was representative of missense p53 mutations. Lighter nuclear staining intensity was observed in up to 40% of cells in areas of hyperplasia and in up to 30% of normal breast lobules irrespective of the type of mutation found in the invasive carcinoma. This weak staining was not specific to mutated p53 and may indicate increased amounts of normal p53 protein.We conclude that p53 inactivation occurs prior to invasion in breast carcinogenesis, with mutations being uniformly identified in DCIS associated with p53-mutated invasive carcinomas. In contrast, there is no evidence that epithelial hyperplasia or epithelial cells of the terminal duct lobular unit harbor the same mutations as their associated invasive carcinoma.     

Tamoxifen Suppresses Histologic Progression to Atypia and DCIS in MCFIOAT Xenografts, a Model of Early Human Breast Cancer

We evaluated the effects of tamoxifen on the growth and progression of MCFIOAT xenografts, an estrogen responsive model of human breast tumor progression, in which cells are injected orthotopically into the mammary fat pad of female nude mice. At 10 weeks following implantation, histologic sections of each graft were evaluated microscopically for histologic lesions analogous to human breast tumor progression, graded as simple hyperplasia, complex hyperplasia, atypical hyperplasia, ductal carcinoma in situ and invasive carcinoma. Three out of five xenografts in (endocrine intact) control animals progressed to atypical hyperplasia, one progressed to ductal carcinoma in situ and one to invasive carcinoma. The latter two control grafts also contained foci of putative precursor lesions (i.e. atypical hyperplasia and in situ carcinoma, respectively). Tamoxifen supplemented xenografts (N=17) were uniformly smaller than controls, but contained invasive carcinoma in a similar proportion (4/17, 24%). However, none of these grafts exhibited ductal carcinoma in situ and only one contained atypical hyperplasia. Most grafts in tamoxifen supplemented animals (10/17, including all four with carcinomas) showed complex hyperplasia, which typically dominated the graft. We conclude that tamoxifen selectively inhibits the appearance or growth of preinvasive index lesions. Development of malignancy in the absence of such precursors, though, implies selection for alternative histogenetic pathways as a result of endocrine manipulation.