拉帕替尼促進HER2neg/low乳癌細胞遷徙能力之探討

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题名:	拉帕替尼促進HER2neg/low乳癌細胞遷徙能力之探討 Lapatinib Facilitates the Migration of HER2neg/low Breast Cancer Cells via EGFR/COX-2 Overexpression in a miR-7-dependent Manner
作者:	蔡欣玲;Shing-Ling Tsai
贡献者:	醫學院癌症生物學研究所
关键词:	乳癌;抗藥性;Breast cancer;Drug resistance;Lapatinib
日期:	2010
上传时间:	2010-09-29 12:15:04 (UTC+8)
摘要:	拉帕替尼 (Lapatinib) 為酪胺酸激酶抑制劑 (Tyrosine Kinase Inhibitor) ，於2007年由美國食品藥物管理局核准為治療晚期或轉移性乳癌之標靶藥物，可抑制第一型 (EGFR) 與第二型 (HER2) 之上皮細胞生長因子受體之活化。大約20-30％之乳癌患者具有第二型上皮細胞生長因子受體過度活化之現象，因此拉帕替尼可有效的延緩該型乳癌病患之病程發展。然而，臨床上發現，使用拉帕替尼治療後約莫6-12個月患者可能會有抗藥性的情形產生，而其中之分子機制目前還未盡全然了解。另一方面，有文獻指出，在HER2大量表現之腫瘤組織中仍然可能存在些許低表現HER2之癌細胞，在此種狀態下，拉帕替尼雖然可有效的殺死HER2大量表現之乳癌細胞，低表現HER2之癌細胞可能不受拉帕替尼抑制，進而成為癌症復發之來源。因此，本研究的主軸在於探討拉帕替尼對於HER2低表現之乳癌細胞的影響。實驗結果顯示，短期處理拉帕替尼於低表現HER2之人類乳腺癌細胞MDA-MB-231，不影響細胞之生長速率。為了模擬臨床上長期投藥後乳癌病人所產生之復發情形，將低表現HER2之人類乳腺癌細胞長期給予拉帕替尼，觀察藥物對於該癌細胞的影響。實驗結果顯示，雖然長期處理拉帕替尼不影響該細胞之生長速率，卻會使其移動 (Migration) 及入侵 (Invasion) 能力增加，而其中之分子機制是透過miR-7表現量下降，促使非活化態之第一型上皮細胞生長因子受體過度表現，造成第二類型環氧化酶(cyclooxgenase-2)的表現增加，進而導致癌細胞之移動與入侵能力增加。因此根據我們的結果顯示，長期給予拉帕替尼可能會透過miR-7-dependent EGFR/COX-2 overexpression pathway，使得HER2低表現之癌細胞之惡性程度增加。拉帕替尼若能合併COX-2抑制劑做合併治療，或許可降低乳癌病人產生復發、甚至是轉移的機率。 Breast cancer is the main cancer in female in the both developed and developing countries. It is also the leading cause of cancer mortality in most countries. Since about 20-30 percent of breast cancers have HER2 overexpression, anti-HER2 target therapies, such as trastuzumab and lapatinib, are developed for HER2 positive breast cancers. Lapatinib is a dual EGFR/HER2 tyrosine kinase inhibitor that has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, acquired resistance to lapatinib occurs within 6-12 months and the underlying molecular mechanisms remain unclear. Although lapatinib can effectively eliminate HER2-positive cells, the minor subpopulation of HER2low/neg cells within the HER2-positive tumors may escape from lapatinib therapy and be the seeds of the recurrent and metastatic lapatinib-refractory tumors. To investigate whether lapatinib has any effect on HER2low/neg cells, we chronically treated HER2-negative MDA-MB-231 breast cancer cells with lapatinib and unexpectedly found that the lapatinib-selected MDA-MB-231 (231/Lap) clones have higher migration and invasion abilities without altering their proliferation rates. The increased migration was due to the cyclooxygenase-2 (COX-2) overexpression, which was mediated by lapatinib-induced EGFR expression independent of its tyrosine kinase activity, and was attenuated by COX-2 inhibitors. Furthermore, the increased EGFR expression in 231/Lap cells was associated with down-regulation of microRNA-7, which was known as an EGFR-3’UTR-targeting microRNA. Treatment of 231/Lap cells with both EGFR siRNA and miR-7 resulted in the decreases in EGFR and COX-2 expressions, cell migration, and invasion. Together, our results revealed that long-term treatment of HER2low/neg cells with lapatinib diminished miR-7 expression, leading to EGFR and COX-2 overexpressions and subsequent increased cell migration. Our findings suggest that co-treatment with COX-2 inhibitors may reduce the metastasis and recurrence of breast tumor in patients who received lapatinib therapy.
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