高度基因異質性與缺乏良好的標靶藥物使得三陰性乳癌的預後非常差。除了基本的手術切除與放射線療法外，紫杉醇/蔥環黴素化療是二、三期三陰性乳癌病人唯一的治療手段。因此，本研究致力於找尋三陰性乳癌的治療標的。有鑒於三陰性乳癌的高度基因異質性可能會導致治療結果不如預期，我們利用k平均分群法將Gene Expression Omnibus mRNA資料庫中的乳癌病患分成四大類。經由比較四種亞型的各基因表現量、各基因對預後的影響、相對應蛋白質在各組織的分佈以及功能評估後，我們認為KIF2C極有潛力成為三陰性乳癌的治療標靶。首先，我們發現KIF2C在四種三陰性乳癌亞型中皆過量表現，在正常人類組織中卻幾乎不表現。此外，擁有較高KIF2C表現量的病患預後通常較差。更重要的是在HeLa細胞中KIF2C對於染色體的正常分離十分重要，缺乏KIF2C會促使細胞凋亡。為了在三陰性乳癌細胞中印證這些臨床的統計結果與先前文獻得到的假說，我們首先檢驗了五株乳癌細胞中的KIF2C表現量，發現其中三株的三陰性乳癌細胞（MDA-MB-231、MDA-MB-468與Hs578T）的KIF2C表現量確實遠高於另外兩株非三陰性乳癌細胞（MCF-7及SK-BR-3）。接著，我們利用shRNA剔除五株乳癌細胞中的KIF2C表現，結果顯示KIF2C缺失會抑制三株三陰性乳癌細胞的成長。另外，藉由縮時攝影顯微技術，我們觀察到KIF2C剔除後的MDA-MB-231細胞長時間停滯於有絲分裂，且最終胞質分裂失敗。有趣的是，我們還發現KIF2C表現量在具紫杉醇抗性的MDA-MB-231細胞中大量提升，且KIF2C缺失會使MDA-MB-231與4T1（鼠源三陰性乳癌細胞）細胞對紫杉醇更加敏感。為了開發新穎且實用的KIF2C抑制劑，我們針對食品藥物監督管理局所核准的藥物以及DHTP類似物進行高通量篩選。結果顯示其中一種由國家衛生研究院謝興邦實驗團隊所合成的DHTP類似物－BPRMC0007S0－不僅能在體外抑制KIF2C活性，更能顯著的抑制MDA-MB-231細胞生長。此外，BPRMC0007S0搭配紫杉醇還能促使細胞加成性死亡（synergistic lethality）。整體而言，我們的研究結果顯示KIF2C對於三陰性乳癌細胞的有絲分裂非常重要，抑制KIF2C可能是治療三陰性乳癌的新策略。

Triple negative breast cancer (TNBC) has the worst clinical outcome among different subtypes of breast cancer due to high interpatient heterogeneity and lack of approved targeted therapies. Systematic chemotherapy is the only approach to treat patients with stage II and III TNBC. Lack of target therapy represents the major unmet medical need for the treatment of TNBC. Aiming to develop a promising therapeutic target for TNBC, we performed data analysis on four clinical subsets of TNBC that were classified from several Gene Expression Omnibus (GEO) breast cancer mRNA expression datasets by k-mean clustering. In combination of gene expression profiles, prognosis, protein expression pattern in human tissues and gene functional evaluation among these four different clinical subsets of TNBC, we identified KIF2C as a primary target. KIF2C is highly expressed in TNBC but nearly undetectable in normal human tissues. High level of KIF2C is associated with poor prognosis. Here, we showed that KIF2C protein expression is relatively high in TNBC cell lines (MDA-MB-231, MDA-MB-468, and Hs578T) when compared to other breast cancer lines (MCF-7, SK-BR-3). The depletion of KIF2C by shRNA suppressed cell growth in MDA-MB-231 cells. With the application of time-lapse live cell microscopy, we found that KIF2C deficiency delayed mitotic progression and impaired cytokinesis in MDA-MB-231 cells. Surprisingly, we found that KIF2C expression level was significantly elevated in paclitaxel-resistant MDA-MB-231 cells. Depletion of KIF2C sensitized MDA-MB-231 and 4T1 to paclitaxel. To develop novel and therapeutically actionable KIF2C inhibitors, we performed KIF2C functional screening on FDA-approved drug library and DHTP analogs. In collaboration with NHRI, we obtained a newly synthesized DHTP analog, BPRMC0007S0. BPRMC0007S0 can strikingly repress cell proliferation in MDA-MB-231. In addition, BPRMC0007S0 induced synergistic lethality together with paclitaxel. In conclusion, our current data indicated that KIF2C plays a vital role in mitotic progression of TNBC, and therefore represents a promising therapeutic target of TNBC.

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