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標題: 雌性激素受體陰性乳癌細胞中探討Her2對於AR的基因表現與調控
Her2 is important to androgen receptor expression and phosphorylation in estrogen receptor negative breast cancer cells
作者: 黃振權
Huang, Chen-Chuan
關鍵字: 雌性激素;Estrogen receptor (ER);雄性激素;人類表皮因子受體;三陰性乳癌;Androgen receptor (AR);Human epidermal growth factor receptor-2 (Her2);Triple-negative breast cancer (TNBC)
出版社: 生命科學系所
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根據行政院衛生署的統計,乳癌為台灣女性好發癌症排名第一位,因此對於乳癌的發生原因以及相關機制的探討成為一個重要的課題。對於癌症治療有許多方法,除了傳統的手術切除及化療之外,標靶治療成為近年來一個新興手段。透過研究了解乳癌細胞在分子生物方面的訊息傳遞路徑,對於標靶治療目標選擇顯得格外重要。在臨床的應用上,Estrogen receptor (ER)、Progesterone Receptor (PR)、Human epidermal growth factor receptor-2 (Her2)為三種常用的分子標誌,研究最為透徹,許多乳癌標靶藥物設計方向,也以拮抗這三種受體為主,例如Tamoxifen (anti-ER)以及Herceptin (anti-Her2)。但是約有12%-20%的乳癌患者,ER、PR、Her2表現皆為陰性,這類病人不僅預後差,腫瘤的惡性程度高並且容易轉移,因此尋找新的分子標靶成為熱門的研究主題。在近年來的研究中,Androgen receptor(AR)被認為是有潛力的乳癌治療標靶對象,不僅從病人的病理組織切片中可以看到AR有過度表現的現象(1),AR的表現與否也與病人的存活率有相關性(2)。承襲本實驗室對於AR的了解,探討AR在乳癌中如何被調控。本研究中發現,在AR受到R1881的活化刺激之後,隨著R1881處理的時間越長,會使得MDA-MB-453細胞株 (ER陰性乳癌細胞)的生長受到抑制,進一步分析蛋白表現則發現Egr-1表現量降低且p27表現量增加。AR可能透過增加p27蛋白基因表現使細胞週期受到抑制而導致癌細胞生長趨緩。AR的上游可被Her2所調控,當Her2活化時能抑制AR-S81的磷酸化,隨著HRG處理時間越長AR-S81磷酸化程度越低,這個磷酸化的位點關係到AR的穩定性,AR-S81磷酸化的降低間接也導致AR趨於不穩定並觀察到總體蛋白量下降。而利用siRNA knockdown Her2的基因表現,也發現AR的表現量隨著給予siRNA的濃度越高而增加。若給予目前的臨床用藥Lapatinib (Her2 inhibitor),在細胞生長受抑制下,則可以發現AR-S81增加且p27蛋白表現量也隨著增加。AR在細胞中的位置也是一個值得探討的議題。從核質分離及免疫染色中的結果顯示,Lapatinib阻斷Her2之後,使得細胞質中的AR蛋白量降低,細胞核中的pS81-AR提高且p27表現量增加。以上結果顯示AR在乳癌細胞中扮演抑制乳癌細胞增生的重要角色且AR的上游可受到Her2的調控。透過了解AR在乳癌中的定位,希望對於未來乳癌的治療方向能所助益。

According to the statistics data, breast cancer is a leading cancer in Taiwan. There are about 2,000 people die of breast cancer every year, and the number of deaths has increased steadily. It is important to find out how does breast cancer begin, develop and metastasis. There are several methods for breast cancer treatment: like surgery, chemotherapy, radiotherapy, hormone therapy and target therapy. Because of the development in molecular biology, we can find the subtle changes by gene chip and analyze which gene is much more active in breast cancer, this gene will be the major target in the treatment of breast cancer, so called target therapy. In the recent studies, Estrogen receptor (ER), Progesterone receptor (PR) and Human epidermal growth factor receptor-2 (Her2) has become the major targets in the treatment of breast cancer. Triple-negative breast cancer (TNBC) accounts for approximately 12%~20% of breast cancers. This subtype of breast cancer lacks expression ER, PR and Her2. TNBC is a poor prognostic factor for disease-free and overall survival; no effective specific targeted therapy is readily available for TNBC. Therefore, to find new molecular target becomes an important research topic, androgen receptor (AR) is one of them. Here we want to discuss the role of AR in breast cancer. The MTT assay and cell counting assay show that AR activation decreased the cell proliferation of MDA-MB-453 cells. it might through the increase of p27 protein level to down-regulation cell cycle. On the other hand, Her2 activation could down-regulate the AR Serine81 phosphorylation and decrease AR protein level. In our previous study, Serine81 (Ser81) is the highest stoichiomertric phosphorylation site on AR and involes in stabilization of AR. Knockdown Her2 expression by siRNA could increase the AR protein level. Use the Her2 inhibitor, Lapatinib also found increases of both AR Ser81 phosphorylation and p27 protein level . All the data show that Her2 is important to androgen receptor expression and phosphorylation in estrogen receptor negative breast cancer cells MDA-MB-453. Finally, we hope to understand the understanding of AR in breast cancer, can contribute to the diagnosis and treatment of breast cancer.
其他識別: U0005-2308201212370600
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