Buformin inhibits the stemness of erbB-2-overexpressing breast cancer cells and premalignant mammary tissues of MMTV-erbB-2 transgenic mice.
Buformin inhibits the stemness of erbB-2-overexpressing breast cancer cells and premalignant mammary tissues of MMTV-erbB-2 transgenic mice.
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DOI：
10.1186/s13046-017-0498-0
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发表时间：
2017-02-13
期刊：
影响因子：
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通讯作者：
Yang X
中科院分区：
文献类型：
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作者：
Parris AB;Zhao Q;Howard EW;Zhao M;Ma Z;Yang X
二甲双胍，一种fda批准的治疗II型糖尿病的药物，已经成为一种很有前途的抗癌药物。其他双胍类似物，包括丁双胍和苯双胍，被认为具有类似的性质。虽然在致癌物模型中，布双胍被证明可以减轻乳腺肿瘤负荷，但布双胍对不同乳腺癌亚型的抗癌作用及其潜在机制尚不清楚。因此，我们旨在通过体外和体内模型研究buformin对erbb -2过表达乳腺癌的影响。使用MTT、细胞周期、克隆/CFC、ALDEFLUOR、肿瘤球和Western blot分析来确定buformin对SKBR3和BT474过表达erbb -2的乳腺癌细胞系的细胞生长、干细胞群、干细胞样特性和信号通路的影响。采用78617个小鼠乳腺肿瘤细胞接种MMTV-erbB-2小鼠，建立了同基因肿瘤细胞移植模型，研究了buformin （1.2 g buformin/kg chow）对肿瘤生长的影响。MMTV-erbB-2小鼠也被喂食布双胍10周，随后分析癌前乳腺组织形态学发育、乳腺上皮细胞（MEC）群和信号通路的变化。Buformin显著抑制SKBR3和BT474细胞的生长，并通过对MMTV-erbB-2小鼠同源肿瘤的显著生长抑制证明了其体内活性。特别是，buformin在体外抑制干细胞群和自我更新，这与抑制受体酪氨酸激酶（RTK）和mTOR信号传导有关。与体外实验结果一致，buformin抑制了MMTV-erbB-2小鼠的乳腺形态发生并降低了细胞增殖。重要的是，buformin减少了来自mm电视- erbb -2小鼠的富含乳腺重建单元（mru）和肿瘤启动细胞（TICs）的MEC群体，这得到了原发性MEC中克隆生成和乳腺球形成受损的支持。我们进一步证明，buformmin介导的MEC干性的体内抑制与mTOR、RTK、ER和β-catenin信号通路的抑制激活有关。总的来说，我们的研究结果为布双胍作为一种有效的抗癌药物选择性靶向tic提供了证据，并为遗传易发erbb -2过表达乳腺癌的患者提供了一种新的预防和/或治疗策略。本文的在线版本（doi:10.1186/s13046-017-0498-0）包含补充材料，可供授权用户使用。
Metformin, an FDA-approved drug for the treatment of Type II diabetes, has emerged as a promising anti-cancer agent. Other biguanide analogs, including buformin and phenformin, are suggested to have similar properties. Although buformin was shown to reduce mammary tumor burden in carcinogen models, the anti-cancer effects of buformin on different breast cancer subtypes and the underlying mechanisms remain unclear. Therefore, we aimed to investigate the effects of buformin on erbB-2-overexpressing breast cancer with in vitro and in vivo models. MTT, cell cycle, clonogenic/CFC, ALDEFLUOR, tumorsphere, and Western blot analyses were used to determine the effects of buformin on cell growth, stem cell populations, stem cell-like properties, and signaling pathways in SKBR3 and BT474 erbB-2-overexpressing breast cancer cell lines. A syngeneic tumor cell transplantation model inoculating MMTV-erbB-2 mice with 78617 mouse mammary tumor cells was used to study the effects of buformin (1.2 g buformin/kg chow) on tumor growth in vivo. MMTV-erbB-2 mice were also fed buformin for 10 weeks, followed by analysis of premalignant mammary tissues for changes in morphological development, mammary epithelial cell (MEC) populations, and signaling pathways. Buformin significantly inhibited SKBR3 and BT474 cell growth, and in vivo activity was demonstrated by considerable growth inhibition of syngeneic tumors derived from MMTV-erbB-2 mice. In particular, buformin suppressed stem cell populations and self-renewal in vitro, which was associated with inhibited receptor tyrosine kinase (RTK) and mTOR signaling. Consistent with in vitro data, buformin suppressed mammary morphogenesis and reduced cell proliferation in MMTV-erbB-2 mice. Importantly, buformin decreased MEC populations enriched with mammary reconstitution units (MRUs) and tumor-initiating cells (TICs) from MMTV-erbB-2 mice, as supported by impaired clonogenic and mammosphere formation in primary MECs. We further demonstrated that buformin-mediated in vivo inhibition of MEC stemness is associated with suppressed activation of mTOR, RTK, ER, and β-catenin signaling pathways. Overall, our results provide evidence for buformin as an effective anti-cancer drug that selectively targets TICs, and present a novel prevention and/or treatment strategy for patients who are genetically predisposed to erbB-2-overexpressing breast cancer. The online version of this article (doi:10.1186/s13046-017-0498-0) contains supplementary material, which is available to authorized users.