Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model

• Published in: PloS one Vol. 7; no. 9; p. e45559
• Main Authors: Buraschi, Simone, Neill, Thomas, Owens, Rick T, Iniguez, Leonardo A, Purkins, George, Vadigepalli, Rajanikanth, Evans, Barry, Schaefer, Liliana, Peiper, Stephen C, Wang, Zi-Xuan, Iozzo, Renato V
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.09.2012; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Animals; Biology; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer genetics; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Cell cycle; Cell Line, Tumor; Cluster Analysis; Coculture Techniques; Cyclin-dependent kinases; Decorin; Decorin - administration & dosage; Decorin - metabolism; Diagnosis; Epidermal growth factor receptors; Epithelial Cells - metabolism; Female; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Humans; Immunomodulation; Kinases; Kruppel-Like Transcription Factors - genetics; Leucine; Medicine; Metastasis; Mice; Pathology; Phosphorylation; Physiological aspects; Proteins; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Reproducibility of Results; Rodents; Signatures; Stroma; Stromal Cells - metabolism; Transcriptome; Transplantation, Heterologous; Tumor Microenvironment - genetics; Tumor Suppressor Proteins - genetics; Tumorigenesis; Tyrosine; Xenografts; United States; Germany; United States > US; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0045559

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties.