Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment
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Wei Bin Fang1, Min Yao1, Gage Brummer1, Diana Acevedo1, Nabil Alhakamy2, Cory Berkland2, Nikki Cheng1
1Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS 66160, USA
2Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA
Nikki Cheng, email: firstname.lastname@example.org
Keywords: CCL2, TAT cell penetrating peptide, breast cancer, macrophage, cancer stem cell
Received: January 20, 2016 Accepted: May 20, 2016 Published: June 7, 2016
Triple negative breast cancers are an aggressive subtype of breast cancer, characterized by the lack of estrogen receptor, progesterone receptor and Her2 expression. Triple negative breast cancers are non-responsive to conventional anti-hormonal and Her2 targeted therapies, making it necessary to identify new molecular targets for therapy. The chemokine CCL2 is overexpressed in invasive breast cancers, and regulates breast cancer progression through multiple mechanisms. With few approaches to target CCL2 activity, its value as a therapeutic target is unclear. In these studies, we developed a novel gene silencing approach that involves complexing siRNAs to TAT cell penetrating peptides (Ca-TAT) through non-covalent calcium cross-linking. Ca-TAT/siRNA complexes penetrated 3D collagen cultures of breast cancer cells and inhibited CCL2 expression more effectively than conventional antibody neutralization. Ca-TAT/siRNA complexes targeting CCL2 were delivered to mice bearing MDA-MB-231 breast tumor xenografts. In vivo CCL2 gene silencing inhibited primary tumor growth and metastasis, associated with a reduction in cancer stem cell renewal and recruitment of M2 macrophages. These studies are the first to demonstrate that targeting CCL2 expression in vivo may be a viable therapeutic approach to treating triple negative breast cancer.
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