Tamoxifen, an important endocrine therapeutic agent, is widely used for the treatment of estrogen receptor positive (ER+) breast cancer. However, de novo or acquired resistance prevents patients from benefitting from endocrine approaches and necessitates alternative treatments. In this study, we report that small heat protein beta-8 (HSPB8) may serve as an important molecule in tamoxifen resistance. HSPB8 expression is enhanced in MCF-7 cells resistant to tamoxifen (MCF-7/R) compared to parent cells. Moreover, high expression of HSPB8 associates with poor prognosis in ER+ breast cancer patients but not in patients without classification. Stimulating ER signaling by heterogeneous expression of ERa or 17β-estradiol promotes HSPB8 expression and reduces the cell population in G1 phase. In contrast, blockage of ER signaling by tamoxifen down-regulates the expression of HSPB8. In addition, knocking down HSPB8 by specific siRNAs induces significant cell cycle arrest at G1 phase. AZD8055 was found to be more potent against the proliferation of MCF-7/R cells than that of parent cells, which was associated with down-regulation of HSPB8. We found that the anti-proliferative activity of AZD8055 was positively correlated with the HSPB8 expression level in ER+ breast cancer cells. Thus, AZD8055 was able to overcome tamoxifen resistance in breast cancer cells, and the expression of HSPB8 may predict the efficacy of AZD8055 in ER+ breast cancer. This hypothesis deserves further investigation.

中文翻译：

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mTOR 抑制剂 AZD8055 通过下调 HSPB8 克服了乳腺癌细胞中的他莫昔芬耐药性。

他莫昔芬是一种重要的内分泌治疗药物，广泛用于治疗雌激素受体阳性（ER+）乳腺癌。然而，新发耐药或获得性耐药会阻止患者从内分泌治疗中获益，因此需要替代治疗。在这项研究中，我们报告小热蛋白β-8 (HSPB8) 可能是他莫昔芬耐药性的重要分子。与亲本细胞相比，对他莫昔芬 (MCF-7/R) 具有抗性的 MCF-7 细胞中的 HSPB8 表达增强。此外，HSPB8 的高表达与 ER+ 乳腺癌患者的不良预后相关，但在未分类的患者中则不然。通过 ERa 或 17β-雌二醇的异质表达刺激 ER 信号传导促进 HSPB8 表达并减少 G1 期的细胞群。相比之下，他莫昔芬阻断 ER 信号通路下调 HSPB8 的表达。此外，通过特定的 siRNA 敲低 HSPB8 会在 G1 期诱导显着的细胞周期停滞。发现 AZD8055 对 MCF-7/R 细胞的增殖比亲代细胞的增殖更有效，这与 HSPB8 的下调有关。我们发现AZD8055的抗增殖活性与ER+乳腺癌细胞中HSPB8的表达水平呈正相关。因此，AZD8055能够克服乳腺癌细胞对他莫昔芬的耐药性，HSPB8的表达可以预测AZD8055在ER+乳腺癌中的疗效。这个假设值得进一步研究。发现 AZD8055 对 MCF-7/R 细胞的增殖比亲代细胞的增殖更有效，这与 HSPB8 的下调有关。我们发现AZD8055的抗增殖活性与ER+乳腺癌细胞中HSPB8的表达水平呈正相关。因此，AZD8055能够克服乳腺癌细胞对他莫昔芬的耐药性，HSPB8的表达可以预测AZD8055在ER+乳腺癌中的疗效。这个假设值得进一步研究。发现 AZD8055 对 MCF-7/R 细胞的增殖比亲代细胞的增殖更有效，这与 HSPB8 的下调有关。我们发现AZD8055的抗增殖活性与ER+乳腺癌细胞中HSPB8的表达水平呈正相关。因此，AZD8055能够克服乳腺癌细胞对他莫昔芬的耐药性，HSPB8的表达可以预测AZD8055在ER+乳腺癌中的疗效。这个假设值得进一步研究。HSPB8的表达可以预测AZD8055在ER+乳腺癌中的疗效。这个假设值得进一步研究。HSPB8的表达可以预测AZD8055在ER+乳腺癌中的疗效。这个假设值得进一步研究。