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通过刺激乳腺癌干细胞扩增促进乳腺癌对他莫昔芬耐药的因素。

Factors Promoting Tamoxifen Resistance in Breast Cancer via Stimulating Breast Cancer Stem Cell Expansion.

作者信息

Ojo Diane, Wei Fengxiang, Liu Yun, Wang Enli, Zhang Hongde, Lin Xiaozeng, Wong Nicholas, Bane Anita, Tang Damu

机构信息

T3310, St. Joseph's Hospital, 50 Charlton Ave East, Hamilton, Ontario, Canada, L8N 4A6.

出版信息

Curr Med Chem. 2015;22(19):2360-74. doi: 10.2174/0929867322666150416095744.

Abstract

Estrogen receptor-alpha positive (ER(+)) breast cancer constitutes 70-75% of the disease incidence. Tamoxifen has been the basis of endocrine therapy for patients with ER(+) breast cancer for more than three decades. The treatment reduces the annual mortality rate of breast cancer by 31%, and remains the most effective targeted cancer therapy. However, approximately one-third of patients treated with adjuvant tamoxifen suffer from aggressive recurrent disease. Resistance to tamoxifen, thus, remains a major challenge in providing effective treatments for these patients. In an effort to overcome the resistance, intensive research has been conducted to understand the underlying mechanisms; this has resulted in the identification of complex factors/pathways contributing to tamoxifen resistance, including modulations of the ERsignaling, upregulation of a set of growth factor receptor networks (HER2, EGFR, FGFR, and IGF1R), alterations of the PI3K-PTEN/AKT/mTOR pathway, and an elevation of the NF-κB signaling. Despite these advances, our understanding of the acquired resistance remains fragmented and there is a lack of a platform to integrate these diversified molecular factors/ pathways into a cohesive mechanistic model. Nonetheless, at the cellular level, it is becoming increasingly recongnized that cancer stem cells (CSCs) are key in driving cancer metastasis and therapy resistance. Likewise, evidence is emerging for the critical contributions of breast cancer stem cells (BCSCs) to tamoxifen resistance. In this review, we will discuss these recent developments of BCSC-mediated resistance to tamoxifen and the contributions of those demonstrated molecular factors/pathways to BCSC expansion during the emergency of tamoxifen resistance.

摘要

雌激素受体α阳性(ER(+))乳腺癌占该疾病发病率的70 - 75%。三十多年来,他莫昔芬一直是ER(+)乳腺癌患者内分泌治疗的基础。这种治疗使乳腺癌的年死亡率降低了31%,并且仍然是最有效的靶向癌症治疗方法。然而,接受辅助性他莫昔芬治疗的患者中约有三分之一会出现侵袭性复发性疾病。因此,对他莫昔芬的耐药性仍然是为这些患者提供有效治疗的主要挑战。为了克服耐药性,人们进行了深入研究以了解其潜在机制;这导致了对导致他莫昔芬耐药的复杂因素/途径的识别,包括ER信号的调节、一组生长因子受体网络(HER2、EGFR、FGFR和IGF1R)的上调、PI3K - PTEN/AKT/mTOR途径的改变以及NF - κB信号的增强。尽管取得了这些进展,我们对获得性耐药的理解仍然支离破碎,并且缺乏一个将这些多样化的分子因素/途径整合到一个连贯的机制模型中的平台。尽管如此,在细胞水平上,人们越来越认识到癌症干细胞(CSCs)是驱动癌症转移和治疗耐药的关键。同样,有证据表明乳腺癌干细胞(BCSCs)对他莫昔芬耐药性也有重要贡献。在这篇综述中,我们将讨论BCSC介导的对他莫昔芬耐药的这些最新进展,以及那些已证实的分子因素/途径在他莫昔芬耐药出现期间对BCSC扩增的贡献。

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