Research Papers:

Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment

Wei Bin Fang, Min Yao, Gage Brummer, Diana Acevedo, Nabil Alhakamy, Cory Berkland and Nikki Cheng _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:49349-49367. https://doi.org/10.18632/oncotarget.9885

Metrics: PDF 3017 views  |   HTML 12204 views  |   ?  


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

Correspondence to:

Nikki Cheng, email: [email protected]

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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 9885