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Tamoxifen differentially regulates miR-29b-1 and miR-29a expression depending on endocrine-sensitivity in breast cancer cells

机译:Tamoxifen差异地调节miR-29b-1和miR-29a表达,取决于乳腺癌细胞的内分泌敏感性

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Endocrine-resistance develops in similar to 40% of breast cancer patients after tamoxifen (TAM) therapy. Although microRNAs are dysregulated in breast cancer, their contribution to endocrine-resistance is not yet understood. Previous microarray analysis identified miR-29a and miR-29b-1 as repressed by TAM in MCF-7 endocrine-sensitive breast cancer cells but stimulated by TAM in LY2 endocrine-resistant breast cancer cells. Here we examined the mechanism for the differential regulation of these miRs by TAM in MCF-7 versus TAM-resistant LY2 and LCC9 breast cancer cells and the functional role of these microRNAs in these cells. Knockdown studies revealed that ER alpha is responsible for TAM regulation of miR-29b-1/a transcription. We also demonstrated that transient overexpression of miR-29b-1/a decreased MCF-7, LCC9, and LY2 proliferation and inhibited LY2 cell migration and colony formation but did not sensitize LCC9 or LY2 cells to TAM. Furthermore, TAM reduced DICER1 mRNA and protein in LY2 cells, a known target of miR-29. Supporting this observation, anti-miR-29b-1 or anti-miR-29a inhibited the suppression of DICER by 4 -OHT . These results suggest miR-29b-1/a has tumor suppressor activity in TAM-resistant cells and does not appear to play a role in mediating TAM resistance. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
机译:内分泌抵抗在他莫昔芬(TAM)治疗后类似于40%的乳腺癌患者。虽然MicroRNA在乳腺癌中具有疑虑,但尚未理解它们对内分泌抵抗的贡献。以前的微阵列分析确定了在MCF-7内分泌敏感乳腺癌细胞中被TAM抑制的miR-29a和miR-29b-1,但是在Ly2内分泌抗性乳腺癌细胞中受到刺激。在这里,我们检查了TAM在MCF-7与TAM抗性Ly2和LCC9乳腺癌细胞中对这些miR的差异调节的机制以及这些微稻草在这些细胞中的功能作用。敲低的研究表明,ERα负责MIR-29B-1 / A转录的TAM调节。我们还证明了MIR-29B-1 / A降低的MCF-7,LCC9和LY2增殖和抑制LY2细胞迁移和菌落形成的瞬时过度表达,但并未将LCC9或LY2细胞对TAM敏化。此外,TAM在Ly2细胞中减少了Dicer1 mRNA和蛋白质,是miR-29的已知靶。支持该观察结果,抗miR-29b-1或抗miR-29a抑制了4 -oht的抑制剂。这些结果表明MIR-29B-1 / A具有抗肿瘤细胞中的肿瘤抑制活性,并且似乎在介导的TAM抗性中发挥作用。 (c)2016 Elsevier Ireland Ltd.保留所有权利。

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