UFR Médecine-INSERM UMRS1310, Université Paris-Saclay, F-94800 Villejuif, France.
Institut Necker Enfants Malades, INSERM UMR-S1151-CNRS UMR-S8253, Université Paris Cité, F-75015 Paris, France.
Cells. 2023 Aug 30;12(17):2176. doi: 10.3390/cells12172176.
(1) Background: Breast cancer is a frequent heterogeneous disorder diagnosed in women and causes a high number of mortality among this population due to rapid metastasis and disease recurrence. Ferroptosis can inhibit breast cancer cell growth, improve the sensitivity of chemotherapy and radiotherapy, and inhibit distant metastases, potentially impacting the tumor microenvironment. (2) Methods: Through data mining, the ferroptosis/extracellular matrix remodeling literature text-mining results were integrated into the breast cancer transcriptome cohort, taking into account patients with distant relapse-free survival (DRFS) under adjuvant therapy (anthracyclin + taxanes) with validation in an independent METABRIC cohort, along with the MDA-MB-231 and HCC338 transcriptome functional experiments with ferroptosis activations (GSE173905). (3) Results: Ferroptosis/extracellular matrix remodeling text-mining identified 910 associated genes. Univariate Cox analyses focused on breast cancer (GSE25066) selected 252 individual significant genes, of which 170 were found to have an adverse expression. Functional enrichment of these 170 adverse genes predicted basal breast cancer signatures. Through text-mining, some ferroptosis-significant adverse-selected genes shared citations in the domain of ECM remodeling, such as TNF, IL6, SET, CDKN2A, EGFR, HMGB1, KRAS, MET, LCN2, HIF1A, and TLR4. A molecular score based on the expression of the eleven genes was found predictive of the worst prognosis breast cancer at the univariate level: basal subtype, short DRFS, high-grade values 3 and 4, and estrogen and progesterone receptor negative and nodal stages 2 and 3. This eleven-gene signature was validated as regulated by ferroptosis inductors (erastin and RSL3) in the triple-negative breast cancer cellular model MDA-MB-231. (4) Conclusions: The crosstalk between ECM remodeling-ferroptosis functionalities allowed for defining a molecular score, which has been characterized as an independent adverse parameter in the prognosis of breast cancer patients. The gene signature of this molecular score has been validated to be regulated by erastin/RSL3 ferroptosis activators. This molecular score could be promising to evaluate the ECM-related impact of ferroptosis target therapies in breast cancer.
(1) 背景：乳腺癌是一种常见的异质性疾病，在女性中诊断出，由于其快速转移和疾病复发，导致该人群死亡率较高。铁死亡可抑制乳腺癌细胞生长，提高化疗和放疗的敏感性，并抑制远处转移，可能影响肿瘤微环境。(2) 方法：通过数据挖掘，将铁死亡/细胞外基质重塑文献的文本挖掘结果整合到乳腺癌转录组队列中，考虑到接受辅助治疗（蒽环类+紫杉类）的患者的无远处复发生存率（DRFS），并在独立的 METABRIC 队列中进行验证，以及 MDA-MB-231 和 HCC338 转录组功能实验中进行铁死亡激活（GSE173905）。(3) 结果：铁死亡/细胞外基质重塑文本挖掘确定了 910 个相关基因。对乳腺癌（GSE25066）进行单变量 Cox 分析，选择了 252 个个体显著基因，其中 170 个基因表达不良。对这些 170 个不良基因的功能富集预测了基底型乳腺癌的特征。通过文本挖掘，一些铁死亡相关的不良选择基因在细胞外基质重塑领域共享引文，如 TNF、IL6、SET、CDKN2A、EGFR、HMGB1、KRAS、MET、LCN2、HIF1A 和 TLR4。基于 11 个基因表达的分子评分发现，在单变量水平上可预测最差的乳腺癌预后：基底亚型、DRFS 短、高分级值 3 和 4 以及雌激素和孕激素受体阴性以及淋巴结分期 2 和 3。该十一基因标志物在三阴性乳腺癌细胞模型 MDA-MB-231 中已被验证为铁死亡诱导剂（erastin 和 RSL3）调节。(4) 结论：细胞外基质重塑-铁死亡功能之间的串扰允许定义一个分子评分，该评分已被表征为乳腺癌患者预后的独立不良参数。该分子评分的基因特征已被验证为受 erastin/RSL3 铁死亡激活剂调节。该分子评分有望评估乳腺癌中铁死亡靶标治疗的细胞外基质相关影响。
