title: Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model.
abstract: 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.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.forename: Rick T
authors.initials: RT
authors.lastname: Owens
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Iniguez
authors.forename: George
authors.initials: G
authors.lastname: Purkins
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Vadigepalli
authors.forename: Barry
authors.initials: B
authors.lastname: Evans
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Zi-Xuan
authors.initials: ZX
authors.lastname: Wang
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018920:Coculture Techniques; D058575:Decorin / Q000008:administration & dosage / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D015203:Reproducibility of Results; D017154:Stromal Cells / Q000378:metabolism; D059467:Transcriptome; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D058575:Decorin; D051741:Kruppel-Like Transcription Factors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins