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首页> 外文期刊>BMC Cancer >A suppressive role of guanine nucleotide-binding protein subunit beta-4 inhibited by DNA methylation in the growth of anti-estrogen resistant breast cancer cells
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A suppressive role of guanine nucleotide-binding protein subunit beta-4 inhibited by DNA methylation in the growth of anti-estrogen resistant breast cancer cells

机译：鸟嘌呤核苷酸结合蛋白亚基β-4在抗雌激素乳腺癌细胞生长中抑制的鸟嘌呤核苷酸结合蛋白亚基β-4的抑制作用

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Breast cancer is the most common malignancy in women worldwide. Although the endocrine therapy that targets estrogen receptor α (ERα) signaling has been well established as an effective adjuvant treatment for patients with ERα-positive breast cancers, long-term exposure may eventually lead to the development of acquired resistance to the anti-estrogen drugs, such as fulvestrant and tamoxifen. A better understanding of the mechanisms underlying antiestrogen resistance and identification of the key molecules involved may help in overcoming antiestrogen resistance in breast cancer. The whole-genome gene expression and DNA methylation profilings were performed using fulvestrant-resistant cell line 182R-6 and tamoxifen-resistant cell line TAMR-1 as a model system. In addition, qRT-PCR and Western blot analysis were performed to determine the levels of mRNA and protein molecules. MTT, apoptosis and cell cycle analyses were performed to examine the effect of either guanine nucleotide-binding protein beta-4 (GNB4) overexpression or knockdown on cell proliferation, apoptosis and cell cycle. Among 9 candidate genes, GNB4 was identified and validated by qRT-PCR as a potential target silenced by DNA methylation via DNA methyltransferase 3B (DNMT3B). We generated stable?182R-6 and TAMR-1 cell lines that are constantly expressing GNB4 and determined the effect of the ectopic GNB4 on cell proliferation, cell cycle, and apoptosis of the antiestrogen-resistant cells in response to either fulvestrant or tamoxifen. Ectopic expression of GNB4 in two antiestrogen resistant cell lines significantly promoted cell growth and shortened cell cycle in the presence of either fulvestrant or tamoxifen. The ectopic GNB4 induced apoptosis in 182R-6 cells, whereas it inhibited apoptosis in TAMR-1 cells. Many regulators controlling cell cycle and apoptosis were aberrantly expressed in two resistant cell lines in response to the enforced GNB4 expression, which may contribute to GNB4-mediated biologic and/or pathologic processes. Furthermore, knockdown of GNB4 decreased growth of both antiestrogen resistant and sensitive breast cancer cells. GNB4 is important for growth of breast cancer cells and a potential target for treatment.
机译：乳腺癌是全世界妇女最常见的恶性肿瘤。虽然靶向雌激素受体α（ERα）信号传导的内分泌治疗已经很好地建立了ERα阳性乳腺癌患者的有效佐剂治疗，但长期暴露可能最终可能导致对抗雌激素药物的获得性抗性的发展，如血糖和他莫昔芬。更好地理解患有抗雌激素抵抗的机制和所涉及的关键分子的鉴定可能有助于克服乳腺癌的抗雌激素。使用含有含量抗性的细胞系182R-6和三氧化细胞系Tamr-1作为模型系统进行全基因组基因表达和DNA甲基化分析。此外，进行QRT-PCR和蛋白质印迹分析以确定mRNA和蛋白质分子的水平。进行MTT，细胞凋亡和细胞周期分析以检查鸟嘌呤核苷酸结合蛋白β-4（GNB4）过表达或敲低对细胞增殖，细胞凋亡和细胞周期的影响。在9个候选基因中，通过DNA甲基转移酶3b（DNMT3B）通过DNA甲基化致密的QRT-PCR鉴定并验证GNB4。我们产生稳定的α182R-6和Tamr-1细胞系，其持续表达GNB4，并确定异位GNB4对抗诱变细胞的细胞增殖，细胞周期和凋亡的效果响应于氟斯特语或他莫昔芬。在两种抗雌诱导细胞系中GNB4的异位表达显着促进了挤出物或他莫昔芬的存在下的细胞生长和缩短细胞周期。异位GNB4在182r-6细胞中诱导细胞凋亡，而它抑制了Tamr-1细胞中的凋亡。控制细胞周期和细胞凋亡的许多调节剂响应于强制性的GNB4表达在两种抗性细胞系中表达，这可能有助于GNB4介导的生物和/或病理过程。此外，GNB4的敲低下降了抗雌激素和敏感的乳腺癌细胞的生长。 GNB4对于乳腺癌细胞的生长和治疗潜在靶标非常重要。

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