Resistance of primary breast cancer cells with enhanced pluripotency and stem cell activity to sex hormonal stimulation and suppression
Resistance of primary breast cancer cells with enhanced pluripotency and stem cell activity to sex hormonal stimulation and suppression
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DOI：
10.1016/j.biocel.2018.10.005
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发表时间：
2018-12-01
影响因子：
4
通讯作者：
Mousa, Noha
中科院分区：
文献类型：
--
作者：
Nasr, Mostafa;Farghaly, Mohamed;Mousa, Noha
女性性类固醇激素在乳腺癌中起着重要作用。同时，目前的证据支持乳腺癌干细胞在癌发生、转移和细胞毒化疗抵抗中的作用。然而，乳腺癌干细胞与性激素或关键激素拮抗剂之间的相互作用仍然是难以捉摸的。目的：探讨不同的性激素刺激和抑制方案对具有干细胞活性的原代人乳腺癌细胞增殖的影响。将细胞连续暴露于雌二醇、孕酮、来曲唑、醋酸乌立妥或醋酸乌立妥-来曲唑的组合6个月。此外，纳米颗粒连接的来曲唑和醋酸乌利司他制剂被纳入随后的短期暴露研究中。结果：所有激素刺激组和抑制组乳腺癌细胞的增殖能力相当（P = 0.8）。此外，纳米颗粒包封的激素拮抗剂不能克服观察到的细胞抗性。细胞表征显示间充质样表型过表达三种主要多能性标志物（Oct 4、SOX 2和Nanog），并且92%的细胞表达ALDH 1A 1。值得注意的是，在重复分析中，CD 44（高）/CD 24（低）细胞群仅占0.97%-5.4%。大多数细胞缺乏间充质标志物的表达，然而，它们表现出成骨和成脂谱系的分化。转移到无血清培养后，长期维持间充质样癌细胞表现出显着的形态可塑性，因为他们迅速切换成上皮样表型与显着的mammosphere形成capacity（P = 0.008）。结论：乳腺癌细胞可以开发一个多能性程序，增强干细胞活性，可能共同有助于普遍抵抗性激素刺激或剥夺。因此，在大型临床研究中分离和表征患者来源的乳腺癌干细胞对于确定内分泌治疗的新靶点至关重要，可能针对干细胞和多能性标记物。这种指导可能有助于克服内分泌抵抗，并引起人们对乳腺癌干细胞在女性整个生殖生命中在内源性和外源性性激素作用下的行为的关注。
Female sex steroid hormones have a fundamental role in breast cancer. Meanwhile, current evidence supports the contribution of breast cancer stem cells in carcinogenesis, metastasis, and resistance to cytotoxic chemotherapy. Nevertheless, the interaction between breast cancer stem cells with sex hormones or key hormonal antagonists remains elusive.Objective: To investigate the effect of diverse sex hormonal stimulation and suppression regimens on the proliferation of a primary human breast cancer cells with stem cell activity.Methods: Cells were exposed to estradiol, progesterone, letrozole, ulipristal acetate, or a combination of ulipristal acetate-letrozole, continually for 6 months. Additionally, nanoparticle-linked letrozole and ulipristal acetate formulations were included in a subsequent short-term exposure study. Phenotypic, pathologic, and functional characteristics of unexposed cells were investigated.Results: The proliferation of breast cancer cells was comparable among all hormonal stimulation and suppression groups (P = 0.8). In addition, the nanoparticle encapsulated hormonal antagonists were not able to overcome the observed resistance of cells. Cell characterization showed a mesenchymal-like phenotype overexpressing three master pluripotency markers (Oct 4, SOX2, and Nanog), and 92% of cells were expressing ALDH1A1. Notably, the CD44(high)/CD24(low) cell population presented only 0.97%-5.4% over repeat analyses. Most cells lacked the expression of mesenchymal markers; however, they showed differentiation into osteogenic and adipogenic lineages. Upon transfer to serum-free culture, the long-term maintained mesenchymal-like cancer cells showed remarkable morphologic plasticity as they switched promptly into an epithelial-like phenotype with significant mammosphere formation capacity (P = 0.008).Conclusion: Breast cancer cells can develop a pluripotent program with enhanced stemness activity that may together contribute to universal resistance to sex hormonal stimulation or deprivation. Isolation and characterization of patient-derived breast cancer stem cells in large clinical studies is therefore crucial to identify new targets for endocrine therapies, potentially directed towards stemness and pluripotency markers. Such direction may help overcoming endocrine resistance and draw attention to breast cancer stem cells' behaviour under endogenous and exogenous sex hormones throughout a woman's reproductive life.