Institute for Molecular Medicine Finland, FIMM, Helsinki Institute for Life Sciences (HiLIFE), University of Helsinki, Helsinki, Finland.
Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
BMC Cancer. 2018 Aug 24;18(1):850. doi: 10.1186/s12885-018-4757-z.
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.
他莫昔芬治疗雌激素受体（ER）阳性乳腺癌可降低 31%的死亡率。然而，超过一半的晚期 ER 阳性乳腺癌对他莫昔芬具有内在抗性，并且大约 40%在治疗期间会获得这种抗性。
为了探索乳腺癌内分泌治疗耐药的机制并寻找新的治疗机会，我们创建了代表腔 A 或腔 B 的他莫昔芬耐药乳腺癌细胞系。通过 RNA-seq 在七个他莫昔芬耐药变体中揭示的基因表达模式与它们的同源亲本细胞进行了比较。我们进一步在公开的患者队列中检查了那些转录组改变。
我们表明，他莫昔芬耐药不能简单地用个别基因的表达改变来解释，这是所有耐药变体的共同机制，或者是新融合基因的出现。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基因表达模式，特别是与胆固醇途径相关。在他莫昔芬耐药的 T-47D 细胞变体中，我们观察到脂滴中的中性脂质明显增加，以及溶酶体中的游离胆固醇积累。耐药细胞也不容易发生溶酶体膜通透性（LMP），并且不易受到针对脂质代谢的化合物的影响。然而，这些细胞对二硫化四乙秋兰姆、LCS-1 和达沙替尼敏感。
总的来说，我们的发现强调了 LMP 预防在他莫昔芬耐药中的重要作用，并提示与这种表型相关的新的药物脆弱性。
