No evidence of significant activity of the multidrug resistance gene product in primary human breast cancer
No evidence of significant activity of the multidrug resistance gene product in primary human breast cancer
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DOI：
10.1023/a:1008255725515
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发表时间：
1998-01-01
影响因子：
50.5
通讯作者：
Hossfeld, DK
中科院分区：
文献类型：
--
作者：
Hegewisch-Becker, S;Staib, F;Hossfeld, DK
背景资料：多药耐药（multidrug resistance，MDR 1）基因产物P-糖蛋白（P-gp）的发现被广泛认为是我们理解耐药细胞出现的临床现象的机制的重要里程碑。MDR 1表达已在许多实体瘤和几乎所有血液恶性肿瘤中显示。然而，关于MDR 1/P-gp在人乳腺癌中表达的结果一直存在争议，并且关于P-gp活性调节的临床试验结果并不令人鼓舞。应用多药耐药基因（MDR 1）逆转录-聚合酶链反应（RT-PCR）、免疫组化和罗丹明123（Rh 123）外排试验，对61例原发性乳腺癌组织中MDR 1/P-gp的表达和P-gp泵的功能进行了研究。用抗P-gp阳性淋巴细胞亚群CD 4、CD 8、CD 56和HER-2/neu基因产物的特异性单克隆抗体分析肿瘤细胞悬液的细胞组成，用于乳腺癌细胞的鉴定。UIC 2和MRK 16分别在72%和75%的样本中显示染色阳性。在62%的样本中检测到MDR 1-RT-PCR阳性信号。然而，免疫组织化学和RT-PCR之间无法建立相关性。HER-2/neu表达与MDR 1-RT-PCR和P-gp免疫组化检测无相关性。分别在100%和84%的肿瘤细胞悬液中建立了CD 8+和CD 4+淋巴细胞的污染。通过Rh 123外排试验评估，CD 8+和CD 4+淋巴细胞表现出显著的P-糖蛋白活性，而在乳腺癌细胞的单个实例中检测不到这种活性。在MDR 1-RT-PCR阳性标本中，CD 8淋巴细胞的平均污染率为4.3%，而在MDR 1 mRNA阴性标本中，CD 8细胞的平均污染率仅为2.4%（P = 0.007）。该信号在通过T细胞玫瑰花环消除淋巴细胞亚群后消失。在原发性乳腺癌中，通过RT-PCR或免疫组化检测MDR 1基因表达并不能指示MDR表型，因为没有证据表明P-gp泵具有显著活性。
Background: The discovery of the multidrug resistance (MDR1) gene product P-glycoprotein (P-gp) has been widely seen as an important milestone in our understanding of the mechanisms underlying the clinical phenomenon of the emergence of resistant cells. MDR1 expression has been shown for numerous solid tumors and for virtually all hematologic malignancies. Nevertheless, results regarding MDR1/P-gp expression in human breast cancer have been controversial and the results of clinical trials on modulation of P-gp activity have not been encouraging.Patients and methods. MDR1/P-gp expression and the function of the P-gp pump were investigated in 61 tumor samples from patients with primary breast cancers by multiparameter analysis using MDR1-RT-PCR, immunohistochemistry with two MAbs (UIC2 and MRK 16) and the rhodamine 123 (Rh123) efflux assay. The cellular composition of the tumor cell suspension was analyzed by using specific MAbs against the P-gp expressing lymphocyte subsets CD4, CD8 and CD56, as well as against the HER-2/neu gene product, which was used to identify breast carcinoma cells.Results. UIC2 and MRK16 revealed a staining positivity in 72% and 75% of samples, respectively. A positive MDR1-RT-PCR signal was detected in 62% of the samples. Nevertheless, no correlation between immunohistochemistry and RT-PCR could be established. Furthermore, there was no correlation between HER-2/neu expression and MDR1-RT-PCR or P-gp immunohistochemical assays. A contamination by CD8+ and CD4+ lymphocytes was established in 100% and 84% of tumor cell suspensions, respectively. As assessed by the Rh123 efflux assay CD8+ and the CD4+ lymphocytes exhibited marked P-glycoprotein activity, whereas such activity was not detectable in a single instance for the breast carcinoma cells. In MDR1-RT-PCR positive samples, contamination by CD8 lymphocytes averaged 4.3%, while the contamination of CD8 cells in the MDR1 mRNA-negative samples was only 2.4% (P = 0.007). This signal vanished after elimination of the lymphocyte subpopulations by T-cell rosetting.Conclusions. In primary breast cancer detection of MDR1 gene expression by means of RT-PCR or immunohistochemical assays is not indicative for the MDR phenotype, since there is no evidence of significant activity of the P-gp pump.