Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer.
Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer.
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DOI：
10.1038/s41388-022-02483-8
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发表时间：
2022-10
期刊：
影响因子：
8
通讯作者：
Ali S
中科院分区：
文献类型：
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作者：
Harrod A;Lai CF;Goldsbrough I;Simmons GM;Oppermans N;Santos DB;Győrffy B;Allsopp RC;Toghill BJ;Balachandran K;Lawson M;Morrow CJ;Surakala M;Carnevalli LS;Zhang P;Guttery DS;Shaw JA;Coombes RC;Buluwela L;Ali S
雌激素受体（ESR1）基因突变在er阳性乳腺癌患者中很常见，这些患者在内分泌治疗中取得进展。大多数突变都集中在激素结合域c端螺旋上或附近的三个残基上，即亮氨酸-536、酪氨酸-537和天冬氨酸-538。为了研究这些突变，我们使用CRISPR-Cas9介导的基因组工程来生成一套全面的等基因突变乳腺癌细胞系。我们的研究结果证实，L536R、Y537C、Y537N、Y537S和D538G突变导致乳腺癌细胞不依赖雌激素生长。生长试验显示突变特异性降低对代表三种临床抗雌激素药物的敏感性。这些不同的突变和药物选择性特征对临床出现内质网突变后的治疗选择具有重要意义。我们的结果进一步表明，突变表达水平可能是某些抗雌激素抵抗程度的决定因素。差异基因表达分析证实了雌激素响应基因的上调，正如预期的那样，但也揭示了干扰素调控基因表达的富集是所有突变的共同特征。最后，从内质网突变细胞的基因表达谱中开发出一个新的基因标记，可以预测内质网突变乳腺癌患者的临床反应。
Mutations in the estrogen receptor (ESR1) gene are common in ER-positive breast cancer patients who progress on endocrine therapies. Most mutations localise to just three residues at, or near, the C-terminal helix 12 of the hormone binding domain, at leucine-536, tyrosine-537 and aspartate-538. To investigate these mutations, we have used CRISPR-Cas9 mediated genome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines. Our results confirm that L536R, Y537C, Y537N, Y537S and D538G mutations confer estrogen-independent growth in breast cancer cells. Growth assays show mutation-specific reductions in sensitivities to drugs representing three classes of clinical anti-estrogens. These differential mutation- and drug-selectivity profiles have implications for treatment choices following clinical emergence of ER mutations. Our results further suggest that mutant expression levels may be determinants of the degree of resistance to some anti-estrogens. Differential gene expression analysis demonstrates up-regulation of estrogen-responsive genes, as expected, but also reveals that enrichment for interferon-regulated gene expression is a common feature of all mutations. Finally, a new gene signature developed from the gene expression profiles in ER mutant cells predicts clinical response in breast cancer patients with ER mutations.
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影响因子：
3
作者：
Bardou P;Mariette J;Escudié F;Djemiel C;Klopp C
通讯作者：
Klopp C
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：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
5.7
作者：
Andreano, Kaitlyn J.;Baker, Jennifer G.;McDonnell, Donald P.
通讯作者：
McDonnell, Donald P.
DOI：
10.1200/jco.22.00338
发表时间：
2022-10-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
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作者：
通讯作者：
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