Jiménez-Garduño Aura M, Mendoza-Rodríguez Mónica G, Urrutia-Cabrera Daniel, Domínguez-Robles María C, Pérez-Yépez Eloy A, Ayala-Sumuano Jorge Tonatiuh, Meza Isaura
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Ciudad de México 07360, Mexico.
Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional 2508, San Pedro Zacatenco, Ciudad de México 07360, Mexico; Universidad Politécnica de Huatusco, Huatusco 94100, Veracruz, Mexico.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):780-785. doi: 10.1016/j.bbrc.2017.06.117. Epub 2017 Jun 20.
Inflammation has been recently acknowledged as a key participant in the physiopathology of oncogenesis and tumor progression. The inflammatory cytokine IL-1β has been reported to induce the expression of markers associated with malignancy in breast cancerous cells through Epithelial-Mesenchymal Transition (EMT). Aggressive breast cancer tumors classified as Triple Negative do not respond to hormonal treatment because they lack three crucial receptors, one of which is the estrogen receptor alpha (ERα). Expression of ERα is then considered a good prognostic marker for tamoxifen treatment of this type of cancer, as the binding of this drug to the receptor blocks the transcriptional activity of the latter. Although it has been suggested that inflammatory cytokines in the tumor microenvironment could regulate ERα expression, the mechanism(s) involved in this process have not yet been established. We show here that, in a cell model of breast cancer cells (6D cells), in which the inflammatory cytokine IL-1β induces EMT by activation of the IL-1β/IL-1RI/β-catenin pathway, the up regulation of TWIST1 leads to methylation of the ESR1 gene promoter. This epigenetic modification produced significant decrease of the ERα receptor levels and increased resistance to tamoxifen. The direct participation of IL-1β in these processes was validated by blockage of the cytokine-induced signaling pathway by wortmannin inactivation of the effectors PI3K/AKT. These results support our previous reports that have suggested direct participation of the inflammatory cytokine IL-1β in the transition to malignancy of breast cancer cells.
炎症最近被认为是肿瘤发生和肿瘤进展病理生理学中的关键参与者。据报道，炎性细胞因子白细胞介素-1β（IL-1β）通过上皮-间质转化（EMT）诱导乳腺癌细胞中与恶性肿瘤相关标志物的表达。归类为三阴性的侵袭性乳腺癌肿瘤对激素治疗无反应，因为它们缺乏三种关键受体，其中之一是雌激素受体α（ERα）。因此，ERα的表达被认为是他莫昔芬治疗这类癌症的良好预后标志物，因为这种药物与受体的结合会阻断后者的转录活性。尽管有人提出肿瘤微环境中的炎性细胞因子可以调节ERα的表达，但这一过程所涉及的机制尚未明确。我们在此表明，在乳腺癌细胞（6D细胞）的细胞模型中，炎性细胞因子IL-1β通过激活IL-1β/IL-1RI/β-连环蛋白途径诱导EMT，TWIST1的上调导致ESR1基因启动子的甲基化。这种表观遗传修饰导致ERα受体水平显著降低，并增加了对他莫昔芬的耐药性。通过渥曼青霉素使效应物PI3K/AKT失活来阻断细胞因子诱导的信号通路，验证了IL-1β在这些过程中的直接参与。这些结果支持了我们之前的报道，即炎性细胞因子IL-1β直接参与乳腺癌细胞向恶性肿瘤的转变。
