乳腺癌、BIRC5与奥氮平

一、整合的高通量转录组数据确定生存素是一种潜在的乳腺癌治疗生物标志物
6 m9 p: Z& y( c7 C8 D% ^) \《Integrated High-throughput Transcriptomic Data Identifies Survivin as a Potential Breast Cancer Therapeutic Biomarker》
) Y% E7 s* k& Q# PMethods: Herein, a comprehensive bioinformatics-based transcriptomics study of breast cancer for identifying differentially expressed genes (DEGs), followed by a screening of potential compounds by molecular docking, was performed. Genome-wide mRNA expression data of breast cancer patients (n=248) and controls (n=65) were retrieved from the GEO database for meta-analysis. Statistically significant DEGs were used for enrichment analysis based on ingenuity pathway analysis and protein-protein network analysis.
Results: A total of 3096 unique DEGs (965 up-regulated and 2131 down-regulated) were mapped as biologically relevant. The most upregulated genes were COL10A1, COL11A1, TOP2A, BIRC5 (survivin), MMP11, S100P, RARA, and the most downregulated genes were ADIPOQ, LEP, CFD, PCK1 and HBA2. Transcriptomic and molecular pathway analyses identified BIRC5/survivin as a significant DEG. Kinetochore metaphase signaling is recognized as a prominent dysregulated canonical pathway. Protein-protein interaction study revealed that KIF2C, KIF20A, KIF23, CDCA8, AURKA, AURKB, INCENP, CDK1, BUB1 and CENPA are BIRC5-associated proteins. Molecular docking was performed to exhibit binding interactions with multiple natural ligands.
, H  U3 b, U* ?% [- R: WConclusion: BIRC5 is a promising predictive marker and a potential therapeutic target in breast cancer. Further large-scale studies are required to correlate the significance of BIRC5 in breast cancer, leading to a step toward the clinical translation of novel diagnostic and therapeutic options.

二、上述论文的结论与几个临床试验结果是相互印证的
# F# g3 ?2 L0 f) Y7 x0 T1、《Clinical significance of the relationship between expression of survivin and effects of neoadjuvant chemotherapy in locally advanced breast cancer》
- X+ z$ E, i' n/ A# ?9 i! IMethods: Neoadjuvant chemotherapy with epirubicin plus paclitaxel was administered to 76 patients in locally advanced breast cancer (including 25 cases of stage IIa, 26 of stage IIb, 16 of stage IIIa, and 9 of stage IIIb), the mean age is 52.8(33-79)years old. All patients were female. They were treated with epirubicin 60 mg/m(2), on day 1, by i. v. followed paclitaxel 175 mg/m(2) by 3 hours continues infusion on day 2 and every 3 weeks repeatedly. Premedication of dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteric and allergic reactions before chemotherapy. Four cycles were used. The expression of survivin in breast cancer tissue was detected with SDS-PAGE, western-immunoblotting and immunohistochemistry (IHC), and then that were immunological stained by anti survivin monoclonal antibody, and also the results were analyzed for the relationship between the expressed intensity of survivin and the effect of neoadjuvant chemotherapy in locally advanced breast cancer patients.
4 ~, _  n% r# x2 kResults: Nineteen out of 76 patients had a clinical complete response, 36 had clinical partial response, and 21 had no change. The response rate was 72.37%(55/76). We found survivin could be differently expressed in 76 patients with SDS-PAGE, western-immunoblotting and IHC and then immune stain by anti survivin monoclonal antibody. Forty six patients were low expressed of survivin and 9 patients were high expressed in all response patients. Eight patients were low expressed, only 1 patient was high expressed of survivin in 9 patients had pCR. But no finding the relationship between the expression of survivin and TNM stage, ER, PgR, HER-2.
Conclusion: The patients have high response rate of low expression of survivin after neoadjuvant chemotherapy with TE regimen in locally advanced breast cancer patients. This results shows that survivin is an important predictive factor for effectiveness of neoadjuvant chemotherapy with TE regimen in locally advanced breast cancer.

2、《Detection of Survivin-expressing circulating cancer cells in the peripheral blood of breast cancer patients by a RT-PCR ELISA》
2 `2 W+ z0 T/ \+ xSurvivin mRNA expression was detected in 69.2%-93.8% of primary breast carcinomas, but is rarely expressed in normal breast tissues and hematopoietic cells. The objective of this study was to investigate the significance that the detection of Survinin-expressing circulating breast cancer cells in the peripheral blood has on clinical outcomes. The detection method was based on a RT-PCR ELISA technique developed in our laboratory. Sixty-seven breast cancer patients in various stages and 135 normal healthy women were investigated. Survivin-expressing circulating cancer cells were detected in the peripheral blood samples from 34 (50.7%) out of 67 breast cancer patients, but not in the healthy women that were used as controls. The presence of Survivin-expressing circulating breast cancer cells was found to be significantly associated with various clinicopathological parameters such as vessel infiltration, histological grade, tumor size, nodal status, ER/PgR status, Her-2 status and clinical stages of the disease (P < 0.01). During a follow-up period of 36 months, 9 out of 11 (81.8%) breast cancer patients that had a positive Survivin-expressing at the time of the initial assay test suffered a relapse of the disease, whereas recurrence was only found in 2 out of 6 (33.3%) breast cancer patients that had a negative Survivin-expression. Thus, the detection of circulating cancer cells expressing Survivin mRNA could provide valuable information for the prediction of metastasis and recurrence of breast cancer.

, d$ m- f4 q$ M" N. y7 W3、《Classical markers like ER and ki-67, but also survivin and pERK, could be involved in the pathological response to gemcitabine, adriamycin and paclitaxel (GAT) in locally advanced breast cancer patients: results from the GEICAM/2002-01 phase II study》
0 B8 h  H- {8 C6 ?% ROur data suggest that not only classical markers (ER, Ki-67), but also survivin and pERK could be involved in the response to GAT, which may contribute to therapy individualisation in future study designs.

三、奥氮平是一种BIRC5抑制剂，可以给抗癌药增敏增效；奥氮平也有止吐、止痛、助眠、增进食欲等作用；奥氮平是抗癌治疗减毒增效的良好辅助用药。
$ n% ^2 i6 m% {" ~《Olanzapine, an Atypical Antipsychotic, Inhibits Survivin Expression and Sensitizes Cancer Cells to Chemotherapeutic Agents》
# Z' }$ n) @3 u. d$ V8 PBackground/aim: Olanzapine, an atypical antipsychotic, is now increasingly used as an off-label indication for the management of cancer patients with chemotherapy-induced nausea and vomiting (CINV). However, how olanzapine affects cancer cells per se remains poorly understood.
8 j6 @$ L7 o* A, }1 i' X# bMaterials and methods: The effects of olanzapine treatment and survivin knockdown, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human cancer cell lines.
/ u& Y! K/ h. h  u# [Results: Olanzapine reduced survivin expression in lung and pancreatic cancer stem cell (CSC) lines and sensitized them to chemotherapeutic agents such as 5-fluorouracil, gemcitabine, and cisplatin in a survivin expression-dependent manner. Olanzapine also reduced survivin expression and chemosensitized serum-cultured, non-CSC ovarian cancer cells that expressed survivin.
Conclusion: Olanzapine may benefit cancer patients not only as an antiemetic for CINV, but also by enhancing the effects of chemotherapeutic agents through down-regulation of survivin, which has been implicated in multidrug chemoresistance.
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