2011-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/654914摘要：雖然亞洲人的乳癌發生率低於西方國家，但是在台灣1960年後出生的婦女，由於飲食文化與生活習慣的急遽西化，最新的統計數據顯示這個年齡層的乳癌罹患率已逐漸追上美國的白人族群。另外，值得注意的是，台灣女性罹患乳癌的平均年齡較白人來得年輕。在西方乳癌患者中僅約25%為停經前婦女；而在台灣則高達50%的乳癌患者為停經前婦女。年輕型乳癌不僅要注重其治療效果，更要著重其預後與復發情形，因為這些因素常常伴隨著生育問題與社交後遺症。目前依臨床病理學可將乳癌分為四型：luminal A, luminal B, HER2-like, basal-like。台灣年輕型乳癌多屬於luminal type (≈70%) 。這類型乳癌的分子病理特徵為受體型酪氨酸激脢HER-2陰性(HER2-ve)、雌性激素受體陽性(estrogen receptor ER+ve)。主要用藥則採ER的拮抗劑-tamoxifen。由於ER是雌性激素訊息傳導途徑中不可或缺的上游分子，這類荷爾蒙療法與男性前列腺癌中阻斷雄性激素(androgen)療法一樣，療程中病人體內荷爾蒙系統的改變、對其它生殖器官所產生的影響、以及對藥物耐受性與抗藥性所引發的各種併發症，均有更待進一步的研究與評估。在此同時，尋找其它專一性更高、療效更快的標靶用藥則是治療台灣女性luminal type乳癌極為迫切的課題。本計劃擬利用新發展出來的「平行巨量轉錄體定序」技術 (RNA-seq)，來找出乳癌細胞中尚未被發現的致癌性融合基因(gene fusion)。 RNA-seq在近幾年內已在前列腺癌的臨床檢體中，鑑定出許多先前未被發現的融合基因。這些融合基因之形成不但與雄性激素受體所調節的轉錄過程息息相關，更重要的是有部份融合基因是「targetable」的。基於這兩種荷爾蒙受體在分子作用機轉有許多相似性，我們推測ER+ve、luminal type的台灣年輕型乳癌細胞中，應有許多致癌性融合基因有待更進一步的發掘。<br> Abstract: Although the incidence rate of breast cancer in Asia is lower than that in Western countries, theincidence rate of breast cancer in Taiwanese women born after the 1960s is approaching that in CaucasianAmericans. Results from epidemiological studies indicate that this dramatic increase may due towesternization of lifestyle and diet, as well as environment effects. In addition, it is notable that the age attumor onset in Taiwanese breast cancer patients is generally younger that that in the Caucasian populations.While close to 25% of patients diagnosed with breast cancer in Western countries are premenopausal, morethan 50% are premenopausal in Taiwanese patients. Young women with breast cancer need to cope withmore complications than their older counterparts, e.g. drug-induced early menopause, childbearing, socialactivities etc. There are four types of breast cancer with distinct molecular and clinicopathological features,namely luminal A, luminal B, HER-2 like and basal-like. Importantly, close to 70% of Taiwanese youngwomen breast cancers are luminal type. Luminal type breast cancers are characterized by receptor tyrosinekinase HER2-ve and estrogen receptor (ER)+ve. Patients diagnosed with these subtypes are systematicallytreated with ER antagonist such as tamoxifen. Similar to androgen ablation in prostate cancer patients,tamoxifen resistant breast cancers are rapidly emerged. In addition, ER/tamoxifen was shown to function aspartial agnoist on endometrium cells thus increases the risk of uterine cancers. These unwanted issues alertthe use of tamoxifen in ER+ve, luminal type breast cancers, and, prompt us to search for alternative targetsfor more specific, potent remedies. Recently, massively parallel transcriptome sequencing (RNA-seq) hasbeen used to identify novel gene fusions (a.k.a. chimera transcripts) in clinical prostate cancer biopsies. Inthe biopsies derived from American prostate cancer patients, close to 50% harbor a fusion between theandrogen-regulated TMPRSS2 and ETS related genes; 1-2 % possess activating, “targetable” fusions of theRAF pathway. Mechanistic studies indicated these gene fusions are likely resulted from the combination ofgenotoxic stress and androgen receptor (AR)-mediated transcription stress in androgen-responsive cells.Because there are many similarities between androgen/AR-mediated and estrogen/ER-mediated-molecularprocesses, here we propose to identify yet-to-be-discovered gene fusions and associated oncogenicpathways in luminal type breast cancers in Taiwan.管腔型乳癌基因融合體轉錄體定序個人化癌症醫療luminal type breast cancergene fusionRNA-Seqpersonalized cancer medicine