Abstract：
Even though tamoxifen has significantly improved the survival of estrogen receptor positive (ER+) mammary carcinoma (MC) patients, the development of drug resistance with consequent disease recurrence has limited its therapeutic efficacy. Trefoil factor-3 (TFF3) has been previously reported to mediate anti-estrogen resistance in ER+MC. Herein, the efficacy of a small molecule inhibitor of TFF3 (AMPC) in enhancing sensitivity and mitigating acquired resistance to tamoxifen in ER+MC cells was investigated. AMPC induced apoptosis of tamoxifen-sensitive and resistant ER+MC cells and significantly reduced cell survival in 2D and 3D culture in vitro. In addition, AMPC reduced cancer stem cell (CSC)-like behavior in ER+MC cells in a BCL2-dependent manner. Synergistic effects of AMPC and tamoxifen were demonstrated in ER+MC cells and AMPC was observed to improve tamoxifen efficacy in tamoxifen-sensitive cells and to re-sensitize cells to tamoxifen in tamoxifen-resistant ER+MC in vitro and in vivo. Additionally, tamoxifen-resistant ER+MC cells were concomitantly resistant to anthracycline, platinum and fluoropyrimidine drugs, but not to Taxanes. Taxane treatment of tamoxifen-sensitive and resistant ER+MC cells increased TFF3 expression indicating a combination vulnerability for tamoxifen-resistant ER+MC cells. Taxanes increased CSC-like behavior of tamoxifen-sensitive and resistant ER+MC cells which was reduced by AMPC treatment. Taxanes synergized with AMPC to promote apoptosis and reduce CSC-like behavior in vitro and in vivo. Hence, AMPC restored the sensitivity of tamoxifen and enhanced the efficacy of Taxanes in tamoxifen-resistant ER+MC. In conclusion, pharmacological inhibition of TFF3 may serve as an effective combinatorial therapeutic strategy for the treatment of tamoxifen-resistant ER+MC.
摘要：
尽管他莫昔芬显著提高了雌激素受体阳性（ER+）乳腺癌（MC）患者的生存率，耐药性的发展以及随之而来的疾病复发限制了其治疗效果。先前已报道三叶因子-3(TFF3)在ER+MC中介导抗雌激素抗性。在这里，在ER+MC细胞中,研究了TFF3(AMPC)的小分子抑制剂在增强敏感性和减轻对他莫昔芬的获得性耐药性方面的功效.AMPC诱导他莫昔芬敏感和耐药的ERMC细胞凋亡，并在体外2D和3D培养中显着降低细胞存活率。此外,AMPC以BCL2依赖性方式降低ER+MC细胞中的癌症干细胞(CSC)样行为。在ERMC细胞中证明了AMPC和他莫昔芬的协同作用，并且在体外和体内观察到AMPC可提高他莫昔芬敏感细胞中他莫昔芬的功效，并使细胞对他莫昔芬耐药ERMC中的他莫昔芬重新敏感。此外,对他莫昔芬耐药的ER+MC细胞同时对蒽环类药物耐药，铂和氟嘧啶药物，但不是Taxanes.紫杉烷处理他莫昔芬敏感性和抗性ER+MC细胞增加TFF3表达,表明他莫昔芬抗性ER+MC细胞的组合脆弱性。紫杉烷类增加了他莫昔芬敏感和抗性ERMC细胞的CSC样行为，而AMPC处理可减少这种行为。紫杉烷与AMPC协同促进细胞凋亡并在体外和体内减少CSC样行为。因此，AMPC恢复了他莫昔芬的敏感性，并增强了紫杉烷在他莫昔芬抗性ERMC中的功效。总之,药物抑制TFF3可作为治疗他莫昔芬耐药ER+MC的有效组合治疗策略.
