Gschwantler-Kaulich Daphne, Weingartshofer Sigrid, Grunt Thomas W, Mairhofer Mario, Tan Yen, Gamper Jutta, Singer Christian F
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
Clinical Division of Oncology, Department of Medicine I, Comprehensive Cancer Center & Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
PLoS One. 2017 Sep 25;12(9):e0185566. doi: 10.1371/journal.pone.0185566. eCollection 2017.
Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro.
Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol.
In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively).
We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.
唑来膦酸（ZA）具有抗骨吸收作用，并可保护早期乳腺癌女性免受骨转移。此外，在内分泌反应性乳腺癌的绝经后女性中，ZA可延长无病生存期（DFS）。确切机制仍不清楚。因此，我们研究了在有无雌二醇的情况下，增加ZA浓度对乳腺癌细胞系的影响，以在体外模拟激素环境。
我们使用细胞增殖检测方法（EZ4U、BrdU）和细胞死亡检测方法（膜联蛋白/碘化丙啶），分析了在0、1和10 nM雌二醇存在的情况下，ZA对两种激素敏感细胞系（MCF-7和T47D）和一种激素不敏感的三阴性细胞系（MDA-MB-231）的剂量依赖性抗增殖和促凋亡作用。
在无雌二醇的情况下，ZA在激素敏感（MCF-7、T47D）和激素不敏感（MDA-MB-231）乳腺癌细胞系中均发挥剂量依赖性抗增殖和促凋亡抗肿瘤作用（p<0.0001）。在有雌二醇的情况下，ZA的抗肿瘤作用仅在激素敏感的MCF-7和T47D细胞系中显著降低（分别为p = 0.0008和p = 0.0008）。
我们已经证明，雌二醇会削弱ZA在激素敏感但非激素不敏感乳腺癌细胞系中的抗增殖和促凋亡作用。我们的研究结果为临床上已证实的ZA对绝经前和绝经后激素敏感早期乳腺癌患者DFS的不同影响提供了一种可能的解释。我们进一步推测，内分泌不敏感肿瘤，如三阴性乳腺癌（TNBC），无论其绝经状态如何，都应从ZA中获益。
