三陰性乳癌的特徵為缺少動情素接受體、黃體素接受體及HER2接受體的表現，大約有15%的乳癌病患屬於此型。三陰性乳癌復發機率較其他類型的乳癌高且較易發生轉移，進而導致死亡率也較高。目前三陰性乳癌的臨床治療大多以化學治療為主，其藥物為紫杉醇類藥物及小紅莓類藥物，但長期使用藥物後，許多病患會產生抗藥性以致治療效果不佳。因此，發展新藥物或是合併其它治療方式是非常重要的。腺病毒E1A基因療法已被運用於乳癌、卵巢癌及頭頸癌的臨床治療試驗，最近研究指出E1A基因治療可以有效的促進腫瘤細胞對化學治療藥物的敏感度。在此，我們證明E1A確實會增強三陰性乳癌對於紫杉醇藥物的敏感度，但其中的分子機制尚未十分明瞭。近年來發現miRNA在許多癌症發展中扮演著重要的角色，其中包含對於化療藥物的抗藥性。在miRNA生合成過程中，Dicer是其中一個必需的酵素，我們發現E1A會增加Dicer的表現量。另外降低Dicer的表現可消除三陰性乳癌細胞對紫杉醇藥物的敏感性，也會增加AXL的表現。我們利用miRNA矩陣分析調查在E1A過度表現且降低Dicer表現時，癌細胞的miRNA表現情形。從這些受到改變的miRNA中找出可能會調控AXL表現的miRNA。我們的研究發現E1A增加Dicer的表現量後，透過調控miR-494抑制AXL蛋白的產生，進而增強三陰性乳癌對紫杉醇藥物的敏感度。因此我們提供關於E1A調控紫杉醇藥物敏感度方面一個新的分子機轉，根據我們的結果顯示Dicer和AXL可能可以做為三陰性乳癌的生物標記。
Triple-negative breast cancer (TNBC) is characterized by a lack of expression of estrogen receptor, progesterone receptor, and HER2, account for approximately 15% of breast cancers. TNBC is associated with poor prognosis and highly metastatic phenotype. Currently, treatments of TNBC are limited to cytotoxic chemotherapy such as paclitaxel and doxorubicin. However, some patients do not respond to these drugs after treatment. The adenovirus type 5 E1A (E1A) gene therapies have been tested in human breast, ovarian, and head and neck tumors clinical trials. Recent studies have shown that E1A is associated with anticancer activities by promoting the sensitivity of tumors cells to anticancer drugs. Here, we demonstrate that E1A can restore the sensitivity of TNBC to paclitaxel. Deregulated miRNAs have been shown to play a critical role in the resistance of cancer cells to chemotherapy. The expression level of Dicer, a miRNA processing enzyme, is increased by E1A. Knockdown of Dicer in E1A-transfected cells abolished E1A-mediated sensitivity to paclitaxel and induced the expression of AXL, a receptor tyrosine kinase associating with poor prognosis. We analyzed the miRNA profiling and found several candidate miRNAs were capable of modulating AXL. In addition, we showed that E1A-mediated upregulation of Dicer can inhibit the expression of AXL through upregulation of miR-494, thereby, to enhance the sensitivity to paclitaxel in TNBC. Our findings indicated a new cascade of E1A-mediated paclitaxel chemosensitization, and suggested that Dicer and AXL may serves as a biomarker for TNBC.
