FGFR4 in endocrine resistance: overexpression and estrogen regulation without direct causative role.

IF 3 3区 医学 Q2 ONCOLOGY
Kai Ding, Lyuqin Chen, Kevin M Levine, Matthew J Sikora, Nilgun Tasdemir, David Dabbs, Rachel Jankowitz, Rachel Hazan, Osama Shah, Jenny Atkinson, Adrian V Lee, Steffi Oesterreich
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引用次数: 0

Abstract

Purpose: Endocrine therapy resistance is the major challenge of managing patients with estrogen receptor positive (ER+) breast cancer. We previously reported frequent overexpression of FGFR4 in endocrine-resistant cell lines and breast cancers that recurred and metastasized following endocrine therapy, suggesting FGFR4 as a potential driver of endocrine resistance. In this study, we investigated the role of FGFR4 in mediating endocrine resistance and explored the therapeutic potential of targeting FGFR4 in advanced breast cancer.

Methods: A gene expression signature of FGFR4 activity was examined in ER+breast cancer pre- and post-neoadjuvant endocrine therapy and the association between FGFR4 expression and patient survival was examined. A correlation analysis was used to uncover potential regulators of FGFR4 overexpression. To investigate if FGFR4 is necessary to drive endocrine resistance, we tested response to FGFR4 inhibition in long-term estrogen-deprived (LTED) cells and their paired parental cells. Doxycycline inducible FGFR4 overexpression and knockdown cell models were generated to examine if FGFR4 was sufficient to confer endocrine resistance. Finally, we examined response to FGFR4 monotherapy or combination therapy with fulvestrant in breast cancer cell lines to explore the potential of FGFR4 targeted therapy for advanced breast cancer and assessed the importance of PAM50 subtype in response to FGFR4 inhibition.

Results: A FGFR4 activity gene signature was significantly upregulated post-neoadjuvant aromatase inhibitor treatment, and high FGFR4 expression predicted poorer survival in patients with ER+breast cancer. Gene expression association analysis using TCGA, METABRIC, and SCAN-B datasets uncovered ER as the most significant gene negatively correlated with FGFR4 expression. ER negatively regulates FGFR4 expression at both the mRNA and protein level across multiple ER+breast cancer cell lines. Despite robust overexpression of FGFR4, LTED cells did not show enhanced responses to FGFR4 inhibition compared to parental cells. Similarly, FGFR4 overexpression and knockdown did not substantially alter response to endocrine treatment in ER+cell lines, nor did FGFR4 and fulvestrant combination treatment show synergistic effects. The HER2-like subtype of breast cancer showed elevated expression of FGFR4 and an increased response to FGFR4 inhibition relative to other breast cancer subtypes.

Conclusions: Despite ER-mediated upregulation of FGFR4 post-endocrine therapy, our study does not support a general role of FGFR4 in mediating endocrine resistance in ER+breast cancer. The significant upregulation of FGFR4 expression in treatment-resistant clinical samples and models following endocrine therapy does not necessarily establish a causal link between the gene and treatment response. Our data suggest that specific genomic backgrounds such as HER2 expression may be required for FGFR4 function in breast cancer and should be further explored.

FGFR4在内分泌抵抗中的过表达和雌激素调节无直接致病作用。
目的:内分泌治疗抵抗是雌激素受体阳性(ER+)乳腺癌患者治疗的主要挑战。我们之前报道了FGFR4在内分泌耐药细胞系和内分泌治疗后复发和转移的乳腺癌中频繁过表达,这表明FGFR4是内分泌耐药的潜在驱动因素。在这项研究中,我们研究了FGFR4在介导内分泌抵抗中的作用,并探索了靶向FGFR4治疗晚期乳腺癌的潜力。方法:在ER+乳腺癌新辅助内分泌治疗前和后检测了FGFR4活性的基因表达特征,并检测了FGFR4表达与患者生存之间的关系。相关分析用于发现FGFR4过表达的潜在调节因子。为了研究FGFR4是否驱动内分泌抵抗是必要的,我们测试了长期雌激素剥夺(LTED)细胞及其配对亲本细胞对FGFR4抑制的反应。生成多西环素诱导的FGFR4过表达和敲低细胞模型,以检查FGFR4是否足以赋予内分泌抗性。最后,我们检测了乳腺癌细胞系对FGFR4单药或氟维司汀联合治疗的反应,以探索FGFR4靶向治疗晚期乳腺癌的潜力,并评估了PAM50亚型对FGFR4抑制反应的重要性。结果:FGFR4活性基因特征在新辅助芳香酶抑制剂治疗后显著上调,高FGFR4表达预测ER+乳腺癌患者的生存率较低。使用TCGA、METABRIC和SCAN-B数据集进行基因表达关联分析发现,ER是与FGFR4表达负相关最显著的基因。在多个ER+乳腺癌细胞系中,ER在mRNA和蛋白水平上负调控FGFR4的表达。尽管FGFR4强烈过表达,但与亲本细胞相比,LTED细胞并未表现出对FGFR4抑制的增强反应。同样,在ER+细胞系中,FGFR4过表达和敲低并没有实质性地改变对内分泌治疗的反应,FGFR4和氟维司汀联合治疗也没有显示协同效应。her2样乳腺癌亚型与其他乳腺癌亚型相比,FGFR4表达升高,对FGFR4抑制的反应增加。结论:尽管内分泌治疗后ER介导的FGFR4上调,但我们的研究并不支持FGFR4在介导ER+乳腺癌内分泌抵抗中的一般作用。在内分泌治疗后的治疗耐药临床样本和模型中,FGFR4表达的显著上调并不一定能建立该基因与治疗反应之间的因果关系。我们的数据表明,特定的基因组背景(如HER2表达)可能需要FGFR4在乳腺癌中的功能,应该进一步探索。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.80
自引率
2.60%
发文量
342
审稿时长
1 months
期刊介绍: Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.
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