乳癌是目前世界上女性癌症病患中為數最多的癌症之ㄧ。腺病毒蛋白type 5 E1A (E1A)和許多抗腫瘤作用有關，曾於多種癌症如乳癌、卵巢癌及頭頸癌之病患進行臨床基因治療試驗。許多的研究指出E1A具有多項抗腫瘤的功能，包括抑制腫瘤的發生、增加腫瘤細胞對於化療藥物的感受性以及減少腫瘤轉移的現象。腫瘤的轉移對於癌症患者的死亡率有極大的影響當然也包括了乳癌的患者。E1A於抑制腫瘤發展的過程中具有多重生物學上的意義，這也促使我們想要釐清E1A抑制癌症的機制。因此，我們對於了解E1A抑制癌症轉移相關的分子機制感到有興趣，並期望藉以作為未來改進乳癌病人臨床試驗的基石。我們初步的實驗結果顯示，E1A可以有效的抑制Glucose-regulated protein 78 (GRP78)這種已被廣泛報導和腫瘤惡化及轉移相關的蛋白的表現。 提出此研究計劃之目的在於詳細探討E1A所造成的抑制癌轉移作用中，GRP78所扮演的生物功能及其調控的機轉。為了達到此目的，我們將著重於E1A如何調控GRP78表現並進而展現對乳癌轉移的抑制作用。以下為此項研究計畫的四大主要目標： 目標一：探討GRP78在E1A所抑制之癌細胞移行及侵入作用中所扮演的角色 目標二：研究E1A抑制GRP78表現之分子機轉 目標三：於動物模式中驗證GRP78的表現對於E1A抗腫瘤作用的影響 目標四：探討GRP78及其相關分子的表現在乳癌病人的臨床重要性 完成以上的主要目標能夠幫助我們對於E1A之抗腫瘤轉移作用建立更加詳細的分子訊息傳遞機制。另外，藉由此研究計畫的新發現也許可以對未來發展癌症治療上提供更多具有潛力的標的物。

Breast cancer is the most diagnose cancer in women. The adenoviral type 5 E1A (E1A) associates with multiple anti-cancer activities and has been tested in multiple clinical trials in a gene therapy setting for breast, ovarian and head and neck cancer patients. Many studies showed that E1A involves in several anti-cancer abilities such as inhibit tumor progression, increase chemo-drugs sensitization and metastasis suppression. Metastasis is the main cause of death for cancer patients, including breast cancer patients. Biological significances of E1A in suppression of cancer progression urgent us to clarify the detail molecular mechanisms of E1A’s anti-cancer activity. Therefore, we are interest in understand the molecular mechanisms that associate with E1A-mediated inhibition of cancer metastasis for potentially improve the clinical trials of breast cancer patients in the future. In our preliminary results, E1A significantly suppressed the expression of Glucose-regulated protein 78 (GRP78), a chaperone protein which has been widely reported that associates with malignancy and metastasis of various types of cancer. The goal of this project is to understand the biological function and regulatory mechanisms of GRP78 in E1A-inhibited metastasis. To reach this goal, we will focus on how E1A regulate the expression of GRP78 and exert suppressive activity of cancer metastasis in breast cancer. Following four specific aims will help us to reveal the goal. SPECIFIC AIM 1: To define the role of GRP78 in E1A-mediated inhibition on cancer cell migration/invasion. SPECIFIC AIM 2: To reveal the molecular mechanisms involved in the regulation of GRP78 by E1A. SPECIFIC AIM 3: To study the biological significance of GRP78 in E1A-mediated metastasis suppression in animal model. SPECIFIC AIM 4: To investigate the clinical significance of GRP78 and related signal molecules in breast cancer patients. Achievements of these specific aims will help us to establish signaling networks to understand better the molecular mechanisms of E1A-mediated inhibition of cancer metastasis. Furthermore, the findings from this project may provide more potential targets to develop novel anti-cancer therapeutic strategies.