Conditional Knockdown of Osteopontin Inhibits Breast Cancer Skeletal Metastasis.

Abstract

High osteopontin (OPN) expression is linked to breast cancer bone metastasis. In this study we modulated osteopontin levels conditionally and investigated any related antineoplastic effects. Therefore, we established cell clones from human breast cancer MDA-MB-231 cells, in which the expression of OPN is regulated by the Tet-Off tet-off system. These cells, which conditionally express a specific miRNA targeting OPN, were used for in vitro studies as well as for a bone metastasis model in nude rats. Changes in whole-genome expression elicited by conditional OPN knockdown and vesicle formation were also analyzed. The alkylphosphocholine erufosine was used for combination therapy. Conditional OPN knockdown caused mild anti-proliferative, but more intensive anti-migratory and anti clonogenic effects, as well as partial and complete remissions of soft tissue and osteolytic lesions. These effects were associated with specific gene and protein expression modulations following miRNA-mediated OPN knockdown. Furthermore, high levels of OPN were detected in vesicles derived from rats harboring breast cancer skeletal metastases. Finally, the combination of OPN inhibition and erufosine treatment caused an additive reduction of OPN levels in the investigated breast cancer cells. Thus, knockdown of OPN alone or in combination with erufosine is a promising strategy in breast cancer skeletal metastasis treatment.

• Authors: Marineta Kovacheva, Michael Zepp, Muriel Schraad, Stefan Berger, Martin R Berger
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 19 (Oct 04 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31590218 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Organophosphates
• Quaternary Ammonium Compounds
• erucylphospho-N,N,N-trimethylpropylammonium
• Osteopontin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Bone Neoplasms (drug therapy, secondary, therapy)
• Breast Neoplasms (drug therapy, pathology, therapy)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Female
• Gene Knockdown Techniques (methods)
• Humans
• Male
• Organophosphates (therapeutic use)
• Osteopontin (genetics, metabolism)
• Quaternary Ammonium Compounds (therapeutic use)
• RNAi Therapeutics (methods)
• Rats
• Rats, Nude