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標題: | EZH2 inhibitors在lapatinib處理之HER2low/neg乳癌細胞抑制轉移作用之探討 EZH2 inhibitors suppress migration of lapatinib-treated HER2low/neg breast cancer cells |
作者: | Chia-Chieh Lin 林家潔 |
指導教授: | 陳青周 |
關鍵字: | 乳癌,轉移,標靶藥物,人類表皮生長因子受體, breast cancer,HER2,lapatinib,EZH2,DZNep, |
出版年 : | 2010 |
學位: | 碩士 |
摘要: | 乳癌是世界上相當普遍的癌症,20%~25%的乳癌之腫瘤會過度表現HER2,此oncoprotein屬於EGFR family,其表現量與癌症之惡性、轉移及較差的存活率相關。Herceptin為最早上市之HER2標靶藥物,可有效延長HER2陽性病患之存活率,Lapatinib為新一代之HER2標靶藥物,為EGFR/HER2之酪胺酸激酶抑制劑,能治療以化療合併Hercetin失敗之乳癌病患,但治療數月後亦會對藥物產生抗藥性而導致腫瘤之復發。IHC之分析發現,HER2陽性之腫瘤內並非均質狀態,HER2陰性之癌細胞雖佔少數,但因不受HER2標靶藥物所抑制,有可能成為日後癌症復發或轉移之來源,先前之研究發現MDA-MB-231此株HER2low/neg細胞長期處理lapatinib後產生之231/lap細胞,其移動及侵入能力顯著上升,顯示lapatinib雖可抑制HER2陽性癌細胞,但也可能惡化HER2陰性癌細胞(Tsai, Shing-Ling 2010)。已知231/lap細胞之COX-2表現有EGFR及p-ERK之參與,我們發現231/lap細胞之EZH2表現較高,且EZH2會增加COX-2之表現,藉由lenti-virus或DZNep抑制EZH2皆可抑制COX-2而降低轉移及侵入,我們也發現DZNep除能抑制EZH2外,也可抑制EGFR之表現及ERK之磷酸化,並且造成cycle arrest及apoptosis,顯示DZNep對這些細胞有治療潛力,因此HER2陽性病患之治療,除了使用lapatinb抑制HER2陽性癌細胞之外,應併用DZNep防止腫瘤內HER2陰性癌細胞之轉移及侵入,以達到更好的抑癌效果。 Breast cancer is a very common cancer around the world and overexpression of HER2 is found in 20-25% of the patients. HER2 is a oncoprotein belongs to EGFR family, and its expression level was associated with advanced disease stage, metastasis and poor survival. Herceptin is the first approved monoclonal antibody for HER2-target therapy, and can effectively prolong the survival of HER2-positive patients. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is a newly small molecule for patients who had received prior chemotherapy and Herceptin. However, there were still patients occurring drug resistance after several months of lapatinib treatment and resulting in tumor recurrence. HER-positive tumors showed heterogenous HER2 expression in IHC analysis, and minor subpopulation of HER2-negative cells may escape from HER2 targeting drugs and may be the seeds for tumor recurrence and metastasis. HER2-negative MDA-MB-231 cells were chronically treated with lapatinib, and MDA-MB-231 (231/lap) clones were derived. These clones show higher migration and invasion abilities due to the overexpression of COX-2, indicating that lapatinib might enhance the aggressiveness of HER2-negative cells during its treatment on HER2-positive breast cancer patients (Tsai, Shing-Ling 2010). EGFR expression and ERK phosphorylation were found to be involved in COX-2 overexpression of 231/lap cells. Here we found that EZH2 was upregulated in 231/lap clones. Lenti-viral shEZH2 to knockdown EZH2 or an EZH2 inhibitor-DZNep effectively decreased COX-2 expression and cell migration and invasion. DZNep could also inhibit EGFR expression and ERK phsphorylation, and induce cell cycle arrest and apoptosis. To improve the outcomes, we suggest that HER2-positive cancer patients who received lapatinib should co-treat with DZNep to reduce the metastasis and recurrence by the HER2-negative cancer cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47687 |
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