title: S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways.
abstract: S100A7/psoriasin, a member of the epidermal differentiation complex, is widely overexpressed in invasive estrogen receptor (ER)α-negative breast cancers. However, it has not been established whether S100A7 contributes to breast cancer growth or metastasis. Here, we report the consequences of its expression on inflammatory pathways that impact breast cancer growth. Overexpression of human S100A7 or its murine homologue mS100a7a15 enhanced cell proliferation and upregulated various proinflammatory molecules in ERα-negative breast cancer cells. To examine in vivo effects, we generated mice with an inducible form of mS100a7a15 (MMTV-mS100a7a15 mice). Orthotopic implantation of MVT-1 breast tumor cells into the mammary glands of these mice enhanced tumor growth and metastasis. Compared with uninduced transgenic control mice, the mammary glands of mice where mS100a7a15 was induced exhibited increased ductal hyperplasia and expression of molecules involved in proliferation, signaling, tissue remodeling, and macrophage recruitment. Furthermore, tumors and lung tissues obtained from these mice showed further increases in prometastatic gene expression and recruitment of tumor-associated macrophages (TAM). Notably, in vivo depletion of TAM inhibited the effects of mS100a7a15 induction on tumor growth and angiogenesis. Furthermore, introduction of soluble hS100A7 or mS100a7a15 enhanced chemotaxis of macrophages via activation of RAGE receptors. In summary, our work used a powerful new model system to show that S100A7 enhances breast tumor growth and metastasis by activating proinflammatory and metastatic pathways.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Mohd W
authors.initials: MW
authors.lastname: Nasser
authors.forename: Zahida
authors.initials: Z
authors.lastname: Qamri
authors.forename: Yadwinder S
authors.initials: YS
authors.lastname: Deol
authors.forename: Janani
authors.initials: J
authors.lastname: Ravi
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Powell
authors.forename: Prashant
authors.initials: P
authors.lastname: Trikha
authors.forename: Reto A
authors.initials: RA
authors.lastname: Schwendener
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
authors.forename: Konstantin
authors.initials: K
authors.lastname: Shilo
authors.forename: Xianghong
authors.initials: X
authors.lastname: Zou
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.forename: Ronald
authors.initials: R
authors.lastname: Wolf
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ganju
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; C506174:S100a7a protein, mouse; D042461:Vascular Endothelial Growth Factor A