Association of tamoxifen resistance and lipid reprogramming in breast cancer.
Association of tamoxifen resistance and lipid reprogramming in breast cancer.
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DOI：
10.1186/s12885-018-4757-z
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发表时间：
2018-08-24
期刊：
影响因子：
3.8
通讯作者：
Kallioniemi O
中科院分区：
文献类型：
--
作者：
Hultsch S;Kankainen M;Paavolainen L;Kovanen RM;Ikonen E;Kangaspeska S;Pietiäinen V;Kallioniemi O
他莫昔芬治疗雌激素受体（ER）阳性乳腺癌可使死亡率降低31%。然而，超过一半的晚期ER阳性乳腺癌对他莫昔芬具有内在耐药性，约40%的晚期ER阳性乳腺癌在治疗期间会获得耐药性。为了探索乳腺癌内分泌治疗耐药的潜在机制并确定新的治疗机会，我们创建了代表管腔A或管腔B的他莫昔芬耐药乳腺癌细胞系。通过RNA测序揭示的7种他莫昔芬耐药变异体的基因表达模式与其同基因亲本细胞进行了比较。我们进一步检查了公开的患者队列中的这些转录组学改变。我们发现，他莫昔芬耐药不能简单地解释为单个基因的表达改变，所有耐药变异体的共同机制，或新的融合基因的出现。相反，耐药细胞系共享与细胞周期、蛋白质修饰和代谢相关的改变的基因表达模式，特别是与胆固醇途径相关的基因表达模式。在他莫昔芬耐药的T-47 D细胞变体中，我们观察到脂滴中中性脂质的显著增加以及溶酶体中游离胆固醇的积累。他莫昔芬耐药细胞也不太容易发生溶酶体膜透化（LMP），并且不容易受到靶向脂质代谢的化合物的影响。然而，细胞对双硫仑、LCS-1和达沙替尼敏感。总之，我们的研究结果强调了LMP预防在他莫昔芬耐药中的重要作用，并提出了与这种表型相关的新药物脆弱性。本文的在线版本（10.1186/s12885-018-4757-z）包含补充材料，可供授权用户使用。
Tamoxifen treatment of estrogen receptor (ER)-positive breast cancer reduces mortality by 31%. However, over half of advanced ER-positive breast cancers are intrinsically resistant to tamoxifen and about 40% will acquire the resistance during the treatment. In order to explore mechanisms underlying endocrine therapy resistance in breast cancer and to identify new therapeutic opportunities, we created tamoxifen-resistant breast cancer cell lines that represent the luminal A or the luminal B. Gene expression patterns revealed by RNA-sequencing in seven tamoxifen-resistant variants were compared with their isogenic parental cells. We further examined those transcriptomic alterations in a publicly available patient cohort. We show that tamoxifen resistance cannot simply be explained by altered expression of individual genes, common mechanism across all resistant variants, or the appearance of new fusion genes. Instead, the resistant cell lines shared altered gene expression patterns associated with cell cycle, protein modification and metabolism, especially with the cholesterol pathway. In the tamoxifen-resistant T-47D cell variants we observed a striking increase of neutral lipids in lipid droplets as well as an accumulation of free cholesterol in the lysosomes. Tamoxifen-resistant cells were also less prone to lysosomal membrane permeabilization (LMP) and not vulnerable to compounds targeting the lipid metabolism. However, the cells were sensitive to disulfiram, LCS-1, and dasatinib. Altogether, our findings highlight a major role of LMP prevention in tamoxifen resistance, and suggest novel drug vulnerabilities associated with this phenotype. The online version of this article (10.1186/s12885-018-4757-z) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
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4.6
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4
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通讯作者：
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影响因子：
6
作者：
Appelqvist, Hanna;Nilsson, Cathrine;Ollinger, Karin
通讯作者：
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影响因子：
11.2
作者：
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