Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI.
Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI.
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DOI：
10.1038/srep34753
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发表时间：
2016-10-07
影响因子：
4.6
通讯作者：
Shapiro DJ
中科院分区：
文献类型：
--
作者：
Mao C;Livezey M;Kim JE;Shapiro DJ
表达ERα突变Y 537 S和D538 G的转移瘤在雌激素受体α（ERα）阳性乳腺癌的内分泌治疗后很常见。用这些突变替换乳腺癌细胞中的野生型ERα的效果尚不清楚。我们使用CRISPR-Cas9基因组编辑系统和同源定向修复来分离和表征14个T47 D细胞系，其中ERα Y 537 S或ERα D538 G替换一个或两个野生型ERα基因。在二维和定量锚定非依赖性三维细胞培养中，ERα Y 537 S和ERα D538 G细胞表现出雌激素非依赖性生长。孕激素进一步增加了它们在微摩尔4-羟基他莫昔芬和氟维司群/ICI 182，780（ICI）中已经显着的增殖。我们最近描述的ERα生物调节剂，BHPI，它过度激活未折叠蛋白反应（UPR），完全阻断增殖。ERα Y 537 S和ERα D538 G细胞中雌激素-ER α靶基因具有组成性活性，部分抗雌激素抗性。在ERα Y 537 S细胞中，UPR标记物sp-XBP 1被组成性激活，并在两种细胞系中被孕酮进一步诱导。与他莫昔芬抗性相关的UPR调节基因，包括致癌分子伴侣BiP/GRP 78，被上调。ICI诱导ERα Y 537 S和ERα D538 G降解的能力降低2倍以上。孕激素、UPR激活和ICI刺激的ERα降解可能减少可能有助于ERα Y 537 S和ERα D538 G细胞中观察到的抗雌激素抵抗。
Outgrowth of metastases expressing ERα mutations Y537S and D538G is common after endocrine therapy for estrogen receptor α (ERα) positive breast cancer. The effect of replacing wild type ERα in breast cancer cells with these mutations was unclear. We used the CRISPR-Cas9 genome editing system and homology directed repair to isolate and characterize 14 T47D cell lines in which ERαY537S or ERαD538G replace one or both wild-type ERα genes. In 2-dimensional, and in quantitative anchorage-independent 3-dimensional cell culture, ERαY537S and ERαD538G cells exhibited estrogen-independent growth. A progestin further increased their already substantial proliferation in micromolar 4-hydroxytamoxifen and fulvestrant/ICI 182,780 (ICI). Our recently described ERα biomodulator, BHPI, which hyperactivates the unfolded protein response (UPR), completely blocked proliferation. In ERαY537S and ERαD538G cells, estrogen-ERα target genes were constitutively active and partially antiestrogen resistant. The UPR marker sp-XBP1 was constitutively activated in ERαY537S cells and further induced by progesterone in both cell lines. UPR-regulated genes associated with tamoxifen resistance, including the oncogenic chaperone BiP/GRP78, were upregulated. ICI displayed a greater than 2 fold reduction in its ability to induce ERαY537S and ERαD538G degradation. Progestins, UPR activation and perhaps reduced ICI-stimulated ERα degradation likely contribute to antiestrogen resistance seen in ERαY537S and ERαD538G cells.
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影响因子：
--
作者：
Andruska, Neal;Mao, Chengjian;Shapiro, David J.
通讯作者：
Shapiro, David J.
影响因子：
7
作者：
Cho SW;Kim S;Kim Y;Kweon J;Kim HS;Bae S;Kim JS
通讯作者：
Kim JS
影响因子：
3.5
作者：
Diep CH;Daniel AR;Mauro LJ;Knutson TP;Lange CA
通讯作者：
Lange CA
DOI：
10.1158/1078-0432.ccr-13-2332
发表时间：
2014-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jeselsohn R;Yelensky R;Buchwalter G;Frampton G;Meric-Bernstam F;Gonzalez-Angulo AM;Ferrer-Lozano J;Perez-Fidalgo JA;Cristofanilli M;Gómez H;Arteaga CL;Giltnane J;Balko JM;Cronin MT;Jarosz M;Sun J;Hawryluk M;Lipson D;Otto G;Ross JS;Dvir A;Soussan-Gutman L;Wolf I;Rubinek T;Gilmore L;Schnitt S;Come SE;Pusztai L;Stephens P;Brown M;Miller VA
通讯作者：
Miller VA
影响因子：
64.5
作者：
Hsu PD;Lander ES;Zhang F
通讯作者：
Zhang F