Fundamental research on the development of treatment for triple negative breast cancer

乳腺癌组织中雌激素受体、孕激素受体和HER 2的表达水平已在临床上常规测量，以预测对内分泌治疗和抗HER 2治疗的反应。不表达这三种受体的乳腺肿瘤被称为三阴性乳腺癌（TNBC）。TNBC对内分泌疗法和抗HER 2疗法均无应答，具有生物学侵袭性，倾向于更早复发，并且预后不良。这些发现促使我们开发针对TNBC的新治疗策略。首先，我们研究了一组人乳腺癌细胞系中与TNBC特征相关的各种基因的蛋白质表达谱。接下来，我们研究了抗肿瘤活性，对细胞周期进程的影响，细胞凋亡和癌症干细胞群体诱导的DNA损伤细胞毒性剂和分子靶向剂在面板中的乳腺癌细胞系。这些实验结果表明，Src信号抑制剂达沙替尼和DNA损伤剂依托泊苷对基底B亚型的乳腺癌细胞显示出有效的抗肿瘤作用，达沙替尼表现出G1-S阻断和细胞凋亡诱导作用，依托泊苷表现出G2/M阻滞和细胞凋亡诱导作用。首次表明达沙替尼降低了推定癌症干细胞的比例。我们还研究了乳腺癌患者中Src信号转导激活的临床意义。本研究的结果表明，Src信号的激活可能会增加乳腺癌细胞的转移潜力。

Expression levels of estrogen receptor, progesterone receptor and HER2 in breast cancer tissues have been routinely measured in clinics to predict responses to endocrine therapy and anti-HER2 therapy. Breast tumors expressing none of these three receptors are named as triple negative breast cancer (TNBC). TNBC responds to neither endocrine therapy nor anti-HER2 therapy, is biologically aggressive, tends to recur earlier, and renders a poor prognosis. These findings prompt us to develop new treatment strategies against TNBC. First, we investigated a protein expression profile of various genes related to TNBC characteristics in a panel of human breast cancer cell lines. Next, we studied antitumor activity, effects on cell cycle progression, apoptosis and cancer stem cell population induced by DNA-damaging cytotoxic agents and molecular targeting agents in the panel of breast cancer cell lines. These experimental results have revealed that a Src signal inhibitor, dasatinib and a DNA-damaging agent, etoposide show potent antitumor effect on breast cancer cells of basal B subtype associated with G1-S blockade and induction of apoptosis for dasatinib or G2/M retardation and induction of apoptosis for etoposide, respectively. It is indicated for the first time that dasatinib reduces a proportion of putative cancer stem cells. We also investigated clinical significance of activation of Src signaling using immunohistochemistry in patients with breast cancer. The results of this study have indicated that activation of Src signaling may increase metastatic potential of breast cancer cells.