Onyeisi Jessica Oyie Sousa, Lopes Carla Cristina, Götte Martin
Department of Gynecology and Obstetrics, Münster University Hospital, Munster, Germany.
Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, Sao Paulo, Brazil.
Am J Physiol Cell Physiol. 2022 Nov 1;323(5):C1345-C1354. doi: 10.1152/ajpcell.00152.2022. Epub 2022 Sep 12.
Expression of the cell surface heparan sulfate proteoglycan syndecan-4 is dysregulated in breast cancer, the most frequent malignancy in women. High expression of syndecan-4 correlates with a worse survival in the subgroup of estrogen receptor negative and estrogen/progesterone-receptor negative patients. Aberrant expression of syndecan-4 in breast cancer involves both transcriptional and posttranscriptional mechanisms, including estrogen- and growth factor-dependent regulation, mutations in , , , and , as well as targeting by microRNAs. At the functional level, syndecan-4 plays an important role in various stages of breast cancer progression by interacting with ligands as diverse as plasma proteins, extracellular matrix proteins, growth factors, and surface receptors, as well as members of the integrin family. Mechanisms including integrin recycling, ectodomain shedding, and crosstalk with other syndecans expand the repertoire of syndecan-4 function. Through these interactions, syndecan-4 regulates cellular processes such as adhesion, migration, and invasion. Additional possible functions of syndecan-4 in cells of the microenvironment contribute to the complexity of its pathophysiology. Notably, syndecan-4 expression is modulated by drugs used in breast cancer treatment, such as trastuzumab and zoledronate. Overall, these findings mark syndecan-4 as a novel pathogenesis factor and promising target for therapeutic interventions in breast cancer.
细胞表面硫酸乙酰肝素蛋白聚糖Syndecan-4的表达在乳腺癌（女性中最常见的恶性肿瘤）中失调。Syndecan-4的高表达与雌激素受体阴性和雌激素/孕激素受体阴性患者亚组中较差的生存率相关。乳腺癌中Syndecan-4的异常表达涉及转录和转录后机制，包括雌激素和生长因子依赖性调节、 、 、 和 的突变，以及微小RNA的靶向作用。在功能水平上，Syndecan-4通过与血浆蛋白、细胞外基质蛋白、生长因子和表面受体以及整合素家族成员等多种配体相互作用，在乳腺癌进展的各个阶段发挥重要作用。包括整合素循环利用、胞外域脱落以及与其他Syndecan相互作用在内的机制扩展了Syndecan-4的功能范围。通过这些相互作用，Syndecan-4调节细胞过程，如黏附、迁移和侵袭。Syndecan-4在微环境细胞中的其他可能功能导致了其病理生理学的复杂性。值得注意的是，Syndecan-4的表达受到乳腺癌治疗中使用的药物（如曲妥珠单抗和唑来膦酸）的调节。总体而言，这些发现标志着Syndecan-4是一种新的发病机制因素，也是乳腺癌治疗干预的有前景的靶点。
