Decorin prevents metastatic spreading of breast cancer.
Metastases in breast cancer are a vital concern in treatment, with epidermal growth factor receptor and ErbB2 strongly implicated in mediating tumor invasion and spreading. In this study, we investigated the role of decorin in suppressing both primary breast carcinomas and pulmonary metastases. We show that decorin causes marked growth suppression both in vitro and in vivo using a metastatic breast cancer cell line and an orthotopic mammary carcinoma model. Treatment with decorin protein core reduced primary tumor growth by 70% and eliminated observed metastases. An adenoviral vector containing the decorin transgene caused primary tumor retardation of 70%, in addition to greatly reducing observed metastases. Moreover, we demonstrate that ErbB2 phosphorylation and total receptor protein levels are reduced in this model system upon de novo expression of decorin under the control of a doxycycline-inducible promoter. Primary tumor growth in vivo was reduced by up to 67% upon decorin induction, and pulmonary metastases were markedly hampered as well. These effects are likely occurring through decorin's long-term downregulation of the ErbB2 tyrosine kinase cascade. These results demonstrate a novel role for decorin in reduction or prevention of tumor metastases in this breast cancer model and could eventually lead to improved therapeutics for metastatic breast cancer.
Reed
Charles C
CC
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Waterhouse
Anna
A
Kirby
Siobhan
S
Kay
Paul
P
Owens
Rick T
RT
McQuillan
David J
DJ
Iozzo
Renato V
RV
D000256:Adenoviridae; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000503:physiopathology*; D010766:Phosphorylation; D011509:Proteoglycans / Q000494:pharmacology*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D018719:Erb-b2 Receptor Tyrosine Kinases; D016212:Transforming Growth Factor beta; C546878:DCN protein, human