OSM-induced CD44 contributes to breast cancer metastatic potential through cell detachment but not epithelial-mesenchymal transition
Received 14 March 2019
Accepted for publication 4 July 2019
Published 15 August 2019 Volume 2019:11 Pages 7721—7737
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Dr Beicheng Sun
Hunter Covert,1 Liliana F Mellor,2,3 Cody L Wolf,1 Nicole Ankenbrandt,1 Jacqueline M Emathinger,2 Ken Tawara,1 Julie Thom Oxford,1,2 Cheryl L Jorcyk1,2
1Boise State University, Biomolecular Sciences Program, Boise, ID 83725, USA; 2Boise State University, Department of Biological Sciences, Boise, ID 83725, USA; 3Oncología Molecular, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid 28029, Spain
Background: 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).
Methods: 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.
Results: 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.
Conclusion: 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.
Keywords: epithelial to mesenchymal transition, Oncostatin M, cluster of differentiation 44, breast tumor metastasis
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