Effects of Neuregulins on Invasion and Metastasis of Non-overexpression ErbB2 Breast Cancer Cells

Objective： To explore the effects of neuregulins on ErbB2 receptor signal transduction pathway activation, and invasion and metastasis of non-overexpression ErbB2 breast cancer cell MDA-MB-231. Methods： The expressions of neuregulin were detected by immunocytochemistry and Western blot. MDA-MB-231 cells were treated with ErbB2 kinase inhibitor AG825. Proliferations were measured with MTT assay. Invasion and metastasis of MDA-ME-231 cells were evaluated with transwell chamber. The enzyme activities of MMP-2 and MMP-9 were detected by gelatin zymography. The expressions of MMP-2 and HIF-1α were detected by Western blot. Results： MDA-MB-231 cells expressed a relatively higher level of neuregulin. In Western blot, the positive reaction band was found at 44KD which coincides with the molecular weight of NRG. When MDA-MB-231 cells were treated with AG825, the proliferation was inhibited in a time-dose-dependent manner （P〈0.01）, invasion and metastasis were also depressed （P〈0.05）. The enzyme activities of MMP-2 and MMP-9 were lower （P〈0.05）. The expression levels of MMP-2 and HIF-lct were decreased （P〈0.05）. Conclusion： Our study indicates that neuregulins are synthesized in MDA-MB-231 cells as transmembrane proteins, neuregulins could activate ErbB2 receptor signal transduction pathway by autocrine or paracrine secretion, and induce invasion and metastasis of MDA-MB-231 cells.

THE EXPRESSION OF CATHEPSIN-D, C-erbB-2 AND EGFR IN BREAST CANCER AND ITS CORRELATION TO LYMPHATIC METASTASIS

The expression of Cathepsin-D(Cath-D),c-erbB-2 and EGFR in breast cancer and its correlation to lymphatic metastases were studied in 277 cases by immunohistochemical technique.Positive staining of CathD was detected in 107 cases(38.62%).Among those, 89cass(83.17%) had documented metastases in the lymph nodes. One hundred and seventy cases(61.38%)stained negative for Cath-D.Of which 64 cases(37.64%)had detectable lymphatic metastases. There is a significant differencd in the rate of the lymphatic metastases between the Cath-D positive and Cath-D negative groups(x2=55 .05 P<0.0001).Fifty-six out of 107 Cath-D positive cases(52.23%)were c-erbB-2 positive as well.However, ouly 27 out of 170 Cath-D ngtive cases(15.88%)were c-erbB-2 positive.The positive mte of c-erbB-2 in Cath-D positive group was significantly different from that of Cath-D negative group (x2=41.58P<0.0001). Among those 107 Cath-D positive cases,49cases(45.79%)were EGFR positive. Only 24 cases (14.12%)were EGFR positive among the 170 Cath-D negative cases. The positive rate of EGFR between these two groups was also significantly different(x2=33.95 P<0.0001).An analysis of the three mentioned markers, the lymph node metastasis and tumor size suggests that Cath-D is the most valuble indicator for tumor aggressiveness. Breast cancer cases with a positive Cath-D staining are more likely to have lymphatic metastases and a poor prognosis.Therefore, alternative therapeutic strategies and close follow ups are appropriate for these patients.

Comparisons between glucose analogue 2-deoxy-2-(^(18)F)fluoro-D-glucose and ^(18)F-sodium fluoride positron emission tomography/computed tomography in breast cancer patients with bone lesions

AIM: To compare 2-deoxy-2-(18F)fluoro-D-glucose(18F-FDG) and 18F-sodium (18F-NaF) positron emission tomography/computed tomography (PET/CT) accuracy in breast cancer patients with clinically/radiologically suspected or known bone metastases.METHODS: A total of 45 consecutive patients with breast cancer and the presence or clinical/biochemical or radiological suspicion of bone metastatic disease underwent 18F-FDG and 18F-fluoride PET/CT. Imaging results were compared with histopathology when available, or clinical and radiological follow-up of at least 1 year. For each technique we calculated: Sensitivity (Se), specificity (Sp), overall accuracy, positive and negative predictive values, error rate, and Youden’s index. McNemar’s χ2 test was used to test the difference in sensitivity and specificity between the two diagnostic methods. All analyses were computed on a patient basis, and then on a lesion basis, with consideration ofthe density of independent lesions on the co-registered CT (sclerotic, lytic, mixed, no-lesions) and the divergent site of disease (skull, spine, ribs, extremities, pelvis). The impact of adding 18F-NaF PET/CT to the work-up of patients was also measured in terms of change in their management due to 18F-NaF PET/CT findings.RESULTS: The two imaging methods of 18F-FDG and 18F-fluoride PET/CT were significantly different at the patient-based analysis: Accuracy was 86.7% and 84.4%, respectively (McNemar’s χ2 = 6.23, df = 1, P = 0.01). Overall, 244 bone lesions were detected in our analysis. The overall accuracy of the two methods was significantly different at lesion-based analysis (McNemar’s χ2 = 93.4, df = 1, P < 0.0001). In the lesion density-based and site-based analysis, 18F-FDG PET/CT provided more accurate results in the detection of CT-negative metastasis (P < 0.002) and vertebral localizations (P < 0.002); 18F-NaF PET/CT was more accurate in detecting sclerotic (P < 0.005) and rib lesions (P < 0.04). 18F-NaF PET/CT led to a change of management in 3 of the 45 patients (6.6%) by revealing findings that were not detected at 18F-FDG PET/CT.CONCLUSION: 18F-FDG PET/CT is a reliable imaging tool in the detection of bone metastasis in most cases, with a diagnostic accuracy that is slightly, but significantly, superior to that of 18F-NaF PET/CT in the general population of breast cancer patients. However, the extremely high sensitivity of 18F-fluoride PET/CT can exploit its diagnostic potential in specific clinical settings (i.e., small CT-evident sclerotic lesions, high clinical suspicious of relapse, and negative 18F-FDG PET and conventional imaging).

Induction of ERBB2 Nuclear Transport after Radiation in Breast Cancer Cells

The ERBB2 nuclear transport in breast cancer cell lines after radiation and its possible role in radiation tolerance were observed. Confocal microscopy and Western blotting were applied to detect the nuclear ERBB2 expression after radiation in breast carcinomas cells. And the effects of Herceptin, AG825 and Cisplatin on the expression of nuclear ERBB2 were investigated. Survival fractions were also observed. After radiation, compared with control group, confocal microscopy and Western blot revealed that the expression of nuclear ERBB2 was increased in breast cancer cells time-dependently. Herceptin, and AG825 could significantly inhibit the radiation-induced nuclear ERBB2 expression, and decrease survival fractions. Cisplatin also induced the nuclear ERBB2 expression in breast cancer cells with high ERBB2 expression. It was concluded that radiation could induce ERBB2 nuclear transport, and nuclear ERBB2 may correlate with radiation resistance in breast cancer cells with high ERBB2 expression.

Lymphangiogenesis as a Prognostic Marker in Breast Cancer Using D2-40 as Lymphatic Endothelial Marker—A Preliminary Study

We studied tumour lymphangiogenesis and lymphatic invasion using D2-40 endothelial marker in 35 breast cancer patients treated by primary surgery and correlated it with various clinico-pathological prognostic parameters. Lymphangiogenesis was quantified using lymphatic micro vessel density (LMVD) by counting the immunostained lymphatic microvessels at 200X. The mean age was 45.97±12.09 years (range 30-80 years). LMVD ranged from 5/hpf to 56/hpf with a mean score of 13.4±10.8 and median of 9. The median value of 9 was taken to classify patients into a low or high LMVD. LMVD correlated significantly with tumour size (p=0.003), histological grade (p=0.046), lymph node status (p=0.030). There was no significant correlation of LMVD with stage, estrogen receptor, progesterone receptor or HER2/neu immunoreactivity. Lymphovascular invasion on D2-40 staining [LVI-D40] was found in 13 (37.1%) cases compared to 6 cases (17.1%) on H & E staining showing a poor agreement (k=0.244). LVI correlated significantly with lymph node status (p=0.011). There was a strong association between tumour size (p=0.142), histological grade (p=0.066) though the correlation was not statistically significant. No correlation was found with stage, estrogen receptor, progesterone receptor or HER2/neu immunoreactivity. The mean LMVD in LVI positive patients was higher (22.85±13.29) as compared to LVI negative patients (7.95±2.05) and this was statistically significant (p=0.001). Increased D2-40 detected LMVD and LVI correlated with poor prognostic parameters.

青年和绝经后女性乳腺癌c-erbB-2、p53、ER和PR受体表达及意义

目的 探讨青年和绝经后女性乳癌c erbB 2、p53、ER、PR的表达及意义。方法 采用SP法检测青年组 (13 1例 )与绝经组 (13 6例 )乳癌组织中各指标的表达及其与临床分期、腋淋巴结 (ALN )转移、3年无病生存率 (DFS)之间的关系。结果 c erbB 2阳性与临床分期、ALN转移相关 (P <0 .0 5) ,c erbB 2阳性者 3年DFS低于阴性者 (P <0 .0 5)。青年组c erbB 2、p53阳性率高、ER阳性率低 (P <0 .0 1) ,3年DFS低于绝经组 (P <0 .0 5)。结论 c erbB 2表达是乳腺癌预后重要指标 ,青年乳腺癌c erbB 2、p53阳性率高 ,ER阳性率低 ,3年DFS低 。

乳腺癌c-erbB-2的表达及其与临床病理指标的关系

目的分析乳腺癌c-erbB-2的表达及其与雌激素受体（ER）、孕激素受体（PR）、腋窝淋巴结、肿瘤大小、病理类型等临床病理指标的关系。方法收集术前未予任何治疗的临床病理资料齐全的原发性乳腺癌病例912例,采用免疫组化法检测c-erbB-2的表达,比较c-erbB-2表达与年龄、肿瘤大小、临床分期、肿瘤部位、绝经状况、腋窝淋巴结、ER、PR、病理类型之间的关系,并结合随访资料分析c-erbB-2的表达是否和预后相关。结果c-erbB-2的阳性率为23%。不同年龄组间c-erbB-2的阳性率差异有统计学意义（P=0.009）,特别是〈35岁组c-erbB-2过表达率高于〉55岁组（P=0.006）;肿块直径〈2 cm、2-5 cm和〉5 cm组间c-erbB-2阳性率差异有统计学意义（P〈0.01）,随肿瘤直径的增加c-erbB-2阳性率增高;腋窝淋巴结无转移、转移1~3个、转移〉3个组间c-erbB-2阳性率差异有统计学意义（P〈0.01）,淋巴结转移〉3个组c-erbB-2的阳性率高于其他两组;ER、PR阴性组c-erbB-2的阳性率高于ER、PR阳性组,差异有统计学意义（P〈0.01）;TMN分期中Ⅲ期c-erbB-2的阳性率高于其他两组,差异有统计学意义（P〈0.05）;在绝经状况、肿瘤部位、病理类型指标中各组c-erbB-2的阳性率无统计学差异。c-erbB-2阳性的乳腺癌患者生存时间明显短于阴性者（P〈0.01）。结论c-erbB-2过表达与肿瘤大小、腋窝淋巴结转移、临床分期呈正相关,与年龄、ERPR呈负相关,与绝经状况、肿瘤部位、病理类型不相关。c-erbB-2是判断乳腺癌预后的良好指标。

乳腺癌组织中C-erbB-2、nm23基因的表达及其预后的关系

目的探讨乳腺癌组织中C-erbB-2基因和nm23基因的表达与预后的关系。方法采用免疫组织化学S-P法检测298例乳腺癌C-erbB-2、nm23基因表达情况并与乳腺癌病理类型、发病年龄、临床分期、腋淋巴结转移情况及5a生存率之间的关系进行分析。结果C-erbB-2基因阳性率36.24%(108/298),nm23基因阳性率为58.05%(173/298);C-erbB-2和nm23基因的表达与肿瘤病理类型、发病年龄、临床分期无明显相关性(P>0.05);C-erbB-2基因表达与腋淋巴结转移呈正相关,与5a生存率呈负相关,nm23基因的表达与腋淋巴结转移呈负相关,与5a生存率呈正相关(P<0.05);C-erbB-2基因表达与nm23基因表达两者之间明显负相关(P<0.05)。结论联合检测乳腺癌组织中C-erbB-2和nm23基因表达可能成为预测、评估乳腺癌患者临床预后的标记物。

乳腺癌钙化灶与ER、PR及c-erbB-2表达的关系

目的探讨乳腺癌钙化灶的特征与乳腺癌组织雌激素受体(ER)、孕激素受体(PR)及癌基因(c-erbB-2)表达的关系。资料与方法观察分析56例乳腺癌钼靶片中微小钙化灶的特征并采用免疫组织化学的方法检测乳腺癌组织中ER、PR及c-erbB-2的表达情况。结果钙化灶呈线样或段样分布的乳腺癌PR阳性率明显低于非线样或段样分布者,两者PR的表达差异有统计学意义(χ2=13.176,P<0.05),而钙化灶的形态、钙化区范围、钙化灶数目、钙化灶的密集度、钙化灶是否合并肿块与ER、PR及c-erbB-2的表达,钙化灶是否呈线样或段样分布与ER及c-erbB-2的表达差异均无统计学意义。结论钙化灶的分布特征与PR表达之间存在一定的相关性,从乳腺癌钼靶片上可粗略预测乳腺癌组织PR的表达情况,从而为临床内分泌治疗、判断疾病的预后等提供依据。

Maspin BCSG1及c-erbB-2表达与乳腺癌预后的关系

目的:探讨Maspin、BCSG1、c-erbB-2蛋白在乳腺癌中的表达及其与预后的关系。方法:选取临床病理资料完整并随访5年以上的137例乳腺癌病例,采用SP免疫组织化学技术检测乳腺癌组织中的Maspin、BCSG1、c-erbB-2蛋白的表达情况,结合临床及病理形态学资料用COX模型分析Maspin、BCSG1、c-erbB-2表达对预后的影响。结果:Maspin、BCSG1、c-erbB-2蛋白在乳腺癌组织中的阳性表达率分别为48.9%,67.2%,27.7%三者与生存时间显著相关(P<0.01)。结论:Maspin、BCSG1、c-erbB-2蛋白在乳腺癌中的表达与患者的生存期密切相关,可作为预测乳腺癌预后的参考指标。

原癌基因蛋白质C-erbB-2在乳腺良恶性病变中表达的意义

目的 :检测原癌基因蛋白质 C- erb B- 2在乳腺良恶性病变中的表达及意义。方法 :对 1 1 1例乳腺良恶性病变的石蜡切片标本进行免疫组织化学染色。结果 :乳腺良恶性病变中乳腺导管内乳头状瘤病的 C- erb B- 2阳性率为 31 .3% ,与乳腺纤维腺病和纤维腺瘤比较差异有显著性 ( P<0 .0 1 ) ,乳腺癌 C- erb B- 2的阳性率为 74.3% ,与良性病变比较差异有显著性 ( P<0 .0 1 ) ;乳腺癌 C- erb B- 2表达与肿瘤大小和组织学分级呈正比 ( P<0 .0 5 ) ,与激素受体 ( ER、PR)水平及 5年生存期呈反比( P<0 .0 5 ) ,与淋巴结是否转移无关。结论 :C- erb B- 2表达的乳腺导管内乳头状瘤病容易癌变 ,C- erb B- 2过度表达的乳腺癌组织分化差、生存期短、预后不好。C- erb B-

乳腺肿瘤癌基因c-erbB-2、c-myc的表达及其临床意义

应用免疫组织化学方法，研究61例乳腺良、恶性病变c－erbB-2、c－myc的癌基因的表达情况。46例乳腺癌中c－erbB－2和c－myc阳性率分别为50％（23／46）和45．7％（21／46）；15例乳腺良性病变中阳性率分别为6．7％（1／15）和53．5％（8／15）．研究发现，c－erbB-2对乳腺良、恶性病变具有一定的鉴别诊断价值，尤其对浸润性导管癌和髓作癌的诊断更有意义，且有淋巴结转移的乳腺癌中的阳性表达率也明显增高．研究表明c－myc的阳性表达率对乳腺肿瘤无鉴别价值，且发现多种临床病理指标也与c－myc表明无显著关联。

乳腺导管原位癌的发病危险因素及生物学指标ER、PR、C-erbB-2表达的研究

目的探讨年龄、初绝经年龄、生育史及哺乳情况等危险因素与乳腺癌发病之间的关系及生物学指标ER、PR、C-erb B-2在乳腺导管原位癌的表达。方法用Logistic回归分析年龄、初潮绝经年龄、生育史及哺乳情况等与乳腺癌发病风险的相关性;同时分析56例乳腺导管原位癌ER、PR、C-erb B-2的表达情况。结果 1在女性的月经、生育、哺乳等因素中,无生育史为乳腺癌发病的危险因素,而哺乳时间长、初潮年龄晚、生产数多则为乳腺癌的保护因素。2乳腺癌组织中ER、PR、C-erb B-2的表达水平明显高于乳腺良性病变。结论女性的月经、生育、哺乳情况与乳腺癌的患病风险有一定关系。通过ER、PR、C-erb B-2表达水平可以对癌组织的生物学行为和预后进行评估,并为内分泌治疗提供依据。

乳腺癌组织中MDR1,TOPOⅡ和C-erbB-2的表达及其相互关系

目的 :探索耐药相关基因MDR1和拓扑异构酶TOPOⅡ在乳腺癌中的表达、与肿瘤标志物的关系及其与临床病理特征的关系 ,同时也探讨MDR1和TOPOⅡ与C -erbB - 2共表达的临床意义。方法 :运用免疫组化方法对 94例乳腺癌组织切片MDR1、TOPOⅡ、C -erbB - 2、EGFR、P5 3、PCNA、nm2 3、ER、PR的表达进行检测。结果 :MDR1、TOPOⅡ和C -erbB - 2在乳腺癌中的阳性率分别为 5 2 .1%、4 8.9%和 4 6 .8% ;MDR1和TOPOⅡ均与C -erbB - 2、EGFR、P5 3有相关关系 ,MDR1还和PCNA有关 ;MDR1和TOPOⅡ单独与各项临床病理特征均无关系 ,但TOPOⅡ与C -erbB - 2或MDR1与C -erbB - 2共表达都与肿瘤大小和临床分期有相关关系 ,尤其是TOPOⅡ与C -erbB - 2共表达相关非常显著。结论 :MDR1和TOPOⅡ不仅是肿瘤多药耐药的重要指标 ,它们与C -erbB - 2共表达在对评价乳腺癌肿瘤大小及临床分期上有重要意义。

c-erbB-2和nm23蛋白在乳腺癌中的表达及其临床意义

目的:探讨c-erbB-2和nm23在乳腺癌中的表达及其与临床预后因素的关系。方法:采用免疫组织化学S-P法检测70例原发性乳腺癌c-erbB-2和nm23蛋白表达,分析其表达水平与乳腺癌病理参数的关系。结果:c-erbB-2蛋白的阳性表达率为45.7%,与年龄、肿瘤大小无明显相关(P>0.05),与腋淋巴结转移及临床分期呈明显正相关(P<0.05)。在组织学分级的比较中,高分化患者阳性率低,中低分化患者c-erbB-2蛋白表达阳性率高,有显著性差异(P<0.05),但中低分化患者之间无明显差异(P>0.05)。nm23蛋白的阳性表达率为68.6%,与临床分期、组织学分级及腋淋巴结转移呈显著负相关,与年龄及肿瘤大小无明显关系。c-erbB-2表达与nm23表达两者之间呈明显负相关(P<0.05)。结论:联合检测乳腺癌组织中c-erbB-2和nm23表达来估计患者预后指导意义更佳。

乳腺癌ER、PR、CerbB-2表达与临床病理的关系

目的探讨乳腺癌患者ER、PR、c-erbB-2的表达,及3者与临床病理因素的相关性。方法采用回顾性分析,通过免疫组织化学方法检测乳腺癌患者ER、PR、c-erbB-2的表达,探讨其与临床的关系(包括患者年龄、肿瘤部位、肿瘤直径、肿瘤所在象限、有无淋巴结转移、临床分期和病理分型),并做统计学处理。结果乳腺癌患者ER阳性率为57.60%(800/1 389),PR阳性率为54.93%(763/1 389),c-erbB-2的阳性率为59.03%(820/1 389)。ER,PR表达与c-erbB-2表达呈负相关,ER与PR表达呈正相关。ER、PR阳性表达与患者肿瘤部位、肿瘤所在象限和病理分型差异无显著性(P>0.05),两者与临床分期和肿瘤直径的差异有显著性(P<0.05),PR阳性表达与患者年龄和有无淋巴结转移差异有显著性(P<0.05)。c-erbB-2阳性表达与患者年龄、肿瘤部位、肿瘤所在象限和临床分期的差异均显著性(P>0.05),但与淋巴结转移、病理分型、肿瘤直径大小的差异有显著性(P<0.05)。结论乳腺癌患者ER、PR、c-erbB-2的检测已广泛应用于临床,3者联合检测有助于乳腺癌患者临床疗效和预后的判断。

乳腺癌组织中Ki67、C-erbB-2、VEGF表达的相关性及临床意义

目的探讨乳腺癌中增殖细胞核抗原(Ki67)、人表皮生长因子-2(C-erbB-2)、血管内皮生长因子(VEGF)的表达与临床病理因素的关系及临床意义。方法采用免疫组化法检测42例乳腺癌标本Ki67、C-erbB-2、VEGF的表达,并与临床病理因素进行相关性分析。结果在42例乳腺癌中,Ki67的表达与乳腺癌临床分期相关(P<0.05);C-erbB-2的表达与乳腺癌临床分期、淋巴结转移状况有关(均P<0.05);VEGF的表达与淋巴结转移状况相关(P<0.05);Ki67和C-erbB-2、Ki67和VEGF的共同表达阳性均与乳腺癌临床分期、淋巴结转移状况显著相关(均P<0.05)。结论Ki67、C-erbB-2和VEGF的阳性表达可以作为乳腺癌发生、发展的评价指标,三者联合检测更加有助于乳腺癌患者的临床治疗和预后判断。

乳腺癌MRI形态学表现与C-erbB-2表达的相关性研究

目的 探讨乳腺癌MRI形态学表现与C erbB 2癌基因的相关性。方法 对 78例乳腺癌和 42例乳腺纤维腺瘤患者术前行乳腺MR扫描 ,分析乳腺癌的MRI形态学表现。术后标本行免疫组织化学染色测定肿瘤细胞C erbB 2的表达情况 ,并分析与相应病灶MRI表现的关系。结果 乳腺癌MRI多表现为边缘形态不规则或毛刺状边缘、边界模糊、瘤内有坏死。乳腺癌内部坏死与癌细胞C erbB 2阳性表达呈显著正相关 (r=0 .2 7,P <0 .0 5 ) ;而边界模糊、毛刺状边缘与癌细胞C erbB 2表达情况无显著相关性 (r =0 .11,r=-0 .13 ,P >0 .0 5 )。结论 乳腺癌MRI形态学表现与分子生物学指标C erbB 2之间存在一定的相关性。乳腺癌的MRI表现从一定程度上反映了癌细胞的生物学行为和预后 ,为临床治疗方案的选择提供客观依据。

乳腺癌ER、PR、p53及c-erbB-2癌基因的多因素分析

目的:探讨乳腺癌组织ER、PR、p53及c-erbB-2癌基因蛋白表达与淋巴结转移、患者年龄及组织学类型的相关性。方法:采用乳腺组织免疫组化SP法检测124例乳腺癌患者中ER、PR、p53及c-erbB-2的表达,并分析其临床意义。结果:ER、PR的阳性表达率与淋巴结转移、患者年龄及组织学类型的无关。(P>0.05),ER、PR与p53及c-erbB-2、表达之间存在负相关性,p53、c-erbB-2阳性表达率与有无淋巴结转移、年龄有关(P<0.05),与组织学类型无关(P>0.05)。结论:ER、PR、p53及c-erbB-2的检测对乳腺癌治疗方案的制定和预后估计有重要临床意义。

莪术油对大鼠乳腺癌癌前病变组织中C-erbB-2、P53表达的影响

目的:通过观察莪术油对大鼠乳腺癌癌前病变组织中C-erbB-2、P53的表达,探讨莪术油治疗乳腺癌癌前病变的机理。方法:275只SD大鼠随机分为空白对照组、疾病模型组、三苯氧胺组、康莱特组及莪术油小、中、大剂量组。采用DMBA诱导乳腺癌癌前病变造模,干预治疗4周,第8至14周分4批处死动物,进行病理学及C-erbB-2、P53免疫组化检测。结果:各试验组不同类型乳腺组织中C-erbB-2、P53表达阳性率呈递增趋势。非典型增生乳腺组织中,各干预组C-erbB-2、P53表达阳性率均明显低于造模对照组(P<0.05),莪术油组低于康莱特组(P<0.05)。结论:莪术油能够降低DMBA诱导大鼠乳腺癌癌前病变组织中癌基因的表达,可能是其阻断乳腺癌发生的有效机制。