CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, Reims, France; Université de Reims Champagne Ardenne, Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France; Biochemistry, Biochemical Analysis & Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.
Department for Life Quality Studies, University of Bologna, Rimini, Italy.
Semin Cancer Biol. 2020 May;62:125-133. doi: 10.1016/j.semcancer.2019.08.003. Epub 2019 Aug 8.
A great hallmark of breast cancer is the absence or presence of estrogen receptors ERα and ERβ, with a dominant role in cell proliferation, differentiation and cancer progression. Both receptors are related with Epithelial-to-Mesenchymal Transition (EMT) since there is a relation between ERs and extracellular matrix (ECM) macromolecules expression, and therefore, cell-cell and cell-ECM interactions. The endocrine resistance of ERα endows epithelial cells with increased aggressiveness and induces cell proliferation, resulting into a mesenchymal phenotype and an EMT status. ERα signaling may affect the transcriptional factors which govern EMT. Knockdown or silencing of ERα and ERβ in MCF-7 and MDA-MB-231 breast cancer cells respectively, provoked pivotal changes in phenotype, cellular functions, mRNA and protein levels of EMT markers, and consequently the EMT status. Mesenchymal cells owe their migratory and invasive properties to invadopodia, while in epithelial cells, lamellipodia and filopodia are mostly observed. Invadopodia, are actin-rich protrusions of plasma membrane, promoting proteolytic degradation of ECM and tumor invasion. Cortactin and MMP-14 govern the formation and principal functions of invadopodia. In vitro experiments proved that lumican inhibits cortactin and MMP-14 expression, alters the formation of lamellipodia and transforms mesenchymal cells into epithelial-like. Conclusively, lumican may inhibit or even reverse the several metastatic features that EMT endows in breast cancer cells. Therefore, a lumican-based anti-cancer therapy which will pharmacologically target and inhibit EMT might be interesting to be developed.
乳腺癌的一个显著特征是雌激素受体 ERα 和 ERβ 的缺失或存在，其在细胞增殖、分化和癌症进展中起主要作用。这两种受体都与上皮间质转化 (EMT) 有关，因为 ERs 与细胞外基质 (ECM) 大分子的表达有关，因此与细胞-细胞和细胞-ECM 相互作用有关。ERα 的内分泌抵抗赋予上皮细胞更高的侵袭性，并诱导细胞增殖，导致间质表型和 EMT 状态。ERα 信号可能会影响调控 EMT 的转录因子。敲低或沉默 MCF-7 和 MDA-MB-231 乳腺癌细胞中的 ERα 和 ERβ，分别引起表型、细胞功能、EMT 标志物的 mRNA 和蛋白水平的重要变化，从而导致 EMT 状态。间质细胞的迁移和侵袭特性归因于侵袭伪足，而在上皮细胞中，主要观察到片状伪足和丝状伪足。侵袭伪足是富含肌动蛋白的质膜突起，促进 ECM 的蛋白水解降解和肿瘤侵袭。桩蛋白和 MMP-14 调控侵袭伪足的形成和主要功能。体外实验证明，亮氨酸拉链蛋白聚糖可抑制桩蛋白和 MMP-14 的表达，改变片状伪足的形成，并将间质细胞转化为上皮样。总之，亮氨酸拉链蛋白聚糖可能抑制甚至逆转 EMT 赋予乳腺癌细胞的几种转移特征。因此，基于亮氨酸拉链蛋白聚糖的抗癌疗法可能具有抑制 EMT 的药理学靶点，值得进一步开发。
