Targeted gene silencing of CCL2 inhibits triple negative breast cancer progression by blocking cancer stem cell renewal and M2 macrophage recruitment.
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.
Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Wei Bin
WB
Fang
Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Min
M
Yao
Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Gage
G
Brummer
Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Diana
D
Acevedo
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA.
Nabil
N
Alhakamy
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA.
Cory
C
Berkland
Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Nikki
N
Cheng
D000818:Animals; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D018932:Chemokine CCL2 / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008264:Macrophages / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009336:Necrosis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D034741:RNA, Small Interfering / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; D003094:Collagen
CCL2; TAT cell penetrating peptide; breast cancer; cancer stem cell; macrophage