2589:氟伐他汀耐药基因标记预防乳腺癌及预测他汀耐药

A. Bhardwaj, Z. Ju, Matthew D Embury, Jing Wang, I. Bedrosian
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The goal of this study is to investigate if the statin mediated upregulation in the cholesterol biosynthesis pathway genes associates with the resistance to fluvastatin in a model of hormonally insensitive breast cancer Methods: A published gene signature of statin resistance was validated 1) a cell line based model of breast cancer progression consisting of inherently fluvastatin sensitive and inherently fluvastatin resistant cell lines and also compared to our experimentally derived acquired signature of fluvastatin resistance using 2) an isogenic set of cell lines consisting of a fluvastatin sensitive cell line (MCF10.AT1), and an acquired resistant cell line (MCF10.AT- R) and lastly validated using 3) SV40 C3 tag, a mouse model of hormone receptor negative breast cancer. Clariom RNA profiling were processed and mined by IPA analysis to identify the fluvastatin resistance signature that were validated by qPCR. 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引用次数: 0

摘要

简介:胆固醇生物合成途径受到高度调控,已知他汀类药物抑制该途径可导致该途径中几个基因的恢复性上调。本研究的目的是探讨在激素不敏感乳腺癌模型中,他汀类药物介导的胆固醇生物合成途径基因上调是否与氟伐他汀耐药性相关。已发表的他汀类药物耐药基因标记得到了验证:1)一个基于细胞系的乳腺癌进展模型,该模型由固有氟伐他汀敏感细胞系和固有氟伐他汀耐药细胞系组成,并与我们通过实验获得的获得性氟伐他汀耐药标记进行了比较;2)一组由氟伐他汀敏感细胞系(MCF10. at1)和获得性耐药细胞系(MCF10)组成的等基因细胞系。AT- R),最后使用SV40 C3标签,激素受体阴性乳腺癌小鼠模型进行验证。通过IPA分析对Clariom RNA谱进行处理和挖掘,鉴定氟伐他汀耐药特征,并通过qPCR验证。通过菌落形成试验和体内乳腺癌小鼠模型测定氟伐他汀的体外耐药性。结果:我们发现,与氟伐他汀敏感的肿瘤前细胞MCF10相比,在已发表的17个基因组中,超过75%的氟伐他汀耐药基因标记(由胆固醇生物合成途径基因组成)在固有耐药细胞系DCIS中显著上调。AT1细胞系。我们发现这种固有的他汀类药物耐药基因特征也与MCF10相关。AT-R抗性细胞我们发现其中13个基因映射到前3个上调途径即类固醇生物合成,类固醇激素生物合成和萜类主干生物合成途径。接下来,我们测试了氟伐他汀治疗小鼠的17个基因他汀耐药信号是否与乳腺肿瘤存在相关,并发现肿瘤乳腺耐药信号中超过50%的基因上调。最后,我们研究了SV40C3标签小鼠(自发性乳腺癌小鼠模型)10天的氟伐他汀治疗是否也可以触发这些胆固醇生物合成途径基因的上调,并提供他汀类药物耐药的早期信号。这些实验表明,10天的时间不足以引起类固醇生物合成途径基因的反馈上调,因此不能用作检测氟伐他汀耐药性的替代时间点。结论:氟伐他汀治疗后多种类固醇生物合成途径基因上调,提示胆固醇生物合成途径可能双重靶向,从而使氟伐他汀耐药乳腺癌细胞增敏。引文格式:Anjana Bhardwaj, Zhenlin Ju, Matthew Embury, Jing Wang, Isabelle Bedrosian。氟伐他汀耐药基因标记预防乳腺癌及预测他汀耐药[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第2589期。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract 2589: Gene signature of fluvastatin resistance for prevention of breast cancer and predicting resistance to statins
Introduction: Cholesterol biosynthesis pathway is highly regulated and inhibition of the pathway with statins is known to cause restorative upregulation of several genes in the pathway. The goal of this study is to investigate if the statin mediated upregulation in the cholesterol biosynthesis pathway genes associates with the resistance to fluvastatin in a model of hormonally insensitive breast cancer Methods: A published gene signature of statin resistance was validated 1) a cell line based model of breast cancer progression consisting of inherently fluvastatin sensitive and inherently fluvastatin resistant cell lines and also compared to our experimentally derived acquired signature of fluvastatin resistance using 2) an isogenic set of cell lines consisting of a fluvastatin sensitive cell line (MCF10.AT1), and an acquired resistant cell line (MCF10.AT- R) and lastly validated using 3) SV40 C3 tag, a mouse model of hormone receptor negative breast cancer. Clariom RNA profiling were processed and mined by IPA analysis to identify the fluvastatin resistance signature that were validated by qPCR. Fluvastatin resistance was determined in vitro by colony formation assay and in vivo in a mouse model of breast cancer. Results: We found more than 75% of the published 17 gene panel fluvastatin resistance gene signature (consisting of cholesterol biosynthesis pathway genes) to be significantly upregulated in an inherently resistant cell line, DCIS cell line, relative to fluvastatin sensitive preneoplastic, MCF10.AT1 cell line. We found this inherent statin resistance gene signature to be also relevant in the MCF10.AT-R resistant cells as we found 13 of these genes to map to top 3 upregulated pathways that are steroid biosynthesis, steroid hormone biosynthesis and terpenoid backbone biosynthesis pathway. Next, we tested if 17 gene statin resistance signature associates with presence of tumors in the mammary glands of fluvastatin treated mice and found upregulation of more than 50% of the genes in the resistance signature in the tumor bearing mammary glands. Lastly, we studied if a 10-day period of fluvastatin treatment to SV40C3 Tag mice, a spontaneous mouse model of breast cancer, can also trigger the upregulation of these cholesterol biosynthesis pathway genes and provide an early signal of statin resistance. These experiments showed that a 10-day period is not long enough to cause a feedback upregulation in steroid biosynthesis pathway genes and thus can9t be used a surrogate timepoint to detect resistance to fluvastatin. Conclusions: Upregulation of multiple steroid biosynthesis pathway genes after fluvastatin treatment suggests an opportunity of dual targeting of the cholesterol biosynthesis pathway in order to sensitize the fluvastatin resistant breast cancer cells. Citation Format: Anjana Bhardwaj, Zhenlin Ju, Matthew Embury, Jing Wang, Isabelle Bedrosian. Gene signature of fluvastatin resistance for prevention of breast cancer and predicting resistance to statins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2589.
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