ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation.
ERα/PR crosstalk is altered in the context of the ERα Y537S mutation and contributes to endocrine therapy-resistant tumor proliferation.
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DOI：
10.1038/s41523-023-00601-7
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发表时间：
2023-11-30
影响因子：
5.9
通讯作者：
Greene, Geoffrey L.
中科院分区：
文献类型：
--
作者：
Huggins, Rosemary J.;Greene, Geoffrey L.
ESR 1 Y 537 S突变通过影响雌激素受体（ERα）基因的调节功能，与内分泌治疗（ET）抵抗和转移性乳腺癌的进展相关。然而，ERα和孕激素受体（PR）之间的复杂关系，称为ERα/PR串扰，尚未在ERα Y 537 S突变的背景下进行表征。使用邻位连接试验，我们确定了ERα Y 537 S突变背景下ERα和PR的物理相互作用增加，包括在细胞核中，这种相互作用可能转化为基因表达的改变。因此，与ERα WT相比，在ERα Y 537 S突变背景下，患者肿瘤和细胞系数据（MCF 7和/或T47 D细胞）中有超过30个基因差异表达。其中，IRS 1是一个突出的目标基因，ERα和PR在染色质结合位点沿着IRS 1的占有率在ERα Y 537 S的背景下发生了独特的改变。此外，IRS 1的siRNA敲除或IRS 1抑制剂NT-157治疗在ERα Y 537 S细胞系中具有显著的抗增殖作用，表明IRS 1是恢复ERα Y 537 S突变乳腺癌患者治疗敏感性的潜在治疗靶点。
The constitutively active ESR1 Y537S mutation is associated with endocrine therapy (ET) resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone receptor (PR), known as ERα/PR crosstalk, has yet to be characterized in the context of the ERα Y537S mutation. Using proximity ligation assays, we identify an increased physical interaction of ERα and PR in the context of the ERα Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ERα Y537S mutation compared to ERα WT. Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 had a significant anti-proliferative effect in ERα Y537S cell lines, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations.
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骨肉瘤细胞系中IRS-1/2 NT157选择性抑制剂的临床前有效性。
影响因子：
5.2
作者：
Garofalo C;Capristo M;Mancarella C;Reunevi H;Picci P;Scotlandi K
通讯作者：
Scotlandi K
影响因子：
5.2
作者：
通讯作者：
--
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：
11.2
作者：
Arnesen S;Blanchard Z;Williams MM;Berrett KC;Li Z;Oesterreich S;Richer JK;Gertz J
通讯作者：
Gertz J
影响因子：
11.4
作者：
KASTNER, P;KRUST, A;CHAMBON, P
通讯作者：
CHAMBON, P