Covert Hunter, Mellor Liliana F, Wolf Cody L, Ankenbrandt Nicole, Emathinger Jacqueline M, Tawara Ken, Oxford Julie Thom, Jorcyk Cheryl L
Boise State University, Biomolecular Sciences Program, Boise, ID 83725, USA.
Boise State University, Department of Biological Sciences, Boise, ID 83725, USA.
Cancer Manag Res. 2019 Aug 15;11:7721-7737. doi: 10.2147/CMAR.S208721. eCollection 2019.
Hormone receptor status in human breast cancer cells is a strong indicator of the aggressiveness of a tumor. Triple negative breast cancers (TNBC) are aggressive, difficult to treat, and contribute to high incidences of metastasis by possessing characteristics such as increased tumor cell migration and a large presence of the transmembrane protein, cluster of differentiation 44 (CD44) on the cell membrane. Estrogen receptor-positive (ER+) cells are less aggressive and do not migrate until undergoing an epithelial-mesenchymal transition (EMT).
The relationship between EMT and CD44 during metastatic events is assessed by observing changes in EMT markers, tumor cell detachment, and migration following cytokine treatment on both parental and CD44 knockdown human breast tumor cells.
ER+ T47D and MCF-7 human breast cancer cells treated with OSM demonstrate increased CD44 expression and CD44 cleavage. Conversely, ER- MDA-MB-231 human breast cancer cells do not show a change in CD44 expression nor undergo EMT in the presence of OSM. In ER+ cells, knockdown expression of CD44 by shRNA did not prevent EMT but did change metastatic processes such as cellular detachment and migration. OSM-induced migration was decreased in both ER+ and ER- cells with shCD44 cells compared to control cells, while the promotion of tumor cell detachment by OSM was decreased in ER+ MCF7-shCD44 cells, as compared to control cells. Interestingly, OSM-induced detachment in ER- MDA-MB-231-shCD44 cells that normally don't detach at significant rates.
OSM promotes both EMT and tumor cell detachment in ER+ breast cancer cells. Yet, CD44 knockdown did not affect OSM-induced EMT in these cells, while independently decreasing OSM-induced cell detachment. These results suggest that regulation of CD44 by OSM is important for at least part of the metastatic cascade in ER+ breast cancer.
人乳腺癌细胞中的激素受体状态是肿瘤侵袭性的一个重要指标。三阴性乳腺癌（TNBC）具有侵袭性，难以治疗，并且由于具有肿瘤细胞迁移增加和细胞膜上大量存在跨膜蛋白分化簇44（CD44）等特征，导致转移发生率很高。雌激素受体阳性（ER+）细胞的侵袭性较低，在经历上皮-间质转化（EMT）之前不会迁移。
通过观察细胞因子处理亲代和CD44基因敲低的人乳腺肿瘤细胞后EMT标志物、肿瘤细胞脱离和迁移的变化，评估转移过程中EMT与CD44之间的关系。
用抑瘤素M（OSM）处理的ER+ T47D和MCF-7人乳腺癌细胞显示CD44表达增加和CD44裂解。相反，ER- MDA-MB-231人乳腺癌细胞在有OSM存在时CD44表达没有变化，也未发生EMT。在ER+细胞中，通过短发夹RNA（shRNA）敲低CD44的表达并不能阻止EMT，但确实改变了转移过程，如细胞脱离和迁移。与对照细胞相比，shCD44细胞的ER+和ER-细胞中OSM诱导的迁移均减少，而与对照细胞相比，ER+ MCF7-shCD44细胞中OSM对肿瘤细胞脱离的促进作用降低。有趣的是，OSM诱导ER- MDA-MB-231-shCD44细胞脱离，而这些细胞通常不会以显著速率脱离。
OSM促进ER+乳腺癌细胞中的EMT和肿瘤细胞脱离。然而，CD44基因敲低并不影响这些细胞中OSM诱导的EMT，同时独立降低OSM诱导的细胞脱离。这些结果表明，OSM对CD44的调节对于ER+乳腺癌转移级联反应的至少一部分很重要。
