title: Presence of insulin-like growth factor binding proteins correlates with tumor-promoting effects of matrix metalloproteinase 9 in breast cancer.
abstract: The stroma of breast cancer can promote the disease's progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV)-Neu] and a triple-negative/basal-like [C3(1)-Simian virus 40 large T antigen (Tag)] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9), an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1)-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1), an MMP9 substrate, were increased in C3(1)-Tag;Mmp9(-/-) compared to C3(1)-Tag;Mmp9(+/+) tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1)-Tag;Mmp9(-/-) mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; The Finsen Laboratory, Rigshospitalet, Copenhagen N, Denmark.
authors.forename: Morten Grønbech
authors.initials: MG
authors.lastname: Rasch
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen N, Denmark.
authors.forename: Ida Katrine
authors.initials: IK
authors.lastname: Lund
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA; University of California, San Francisco, San Francisco, CA, USA. Electronic address: egeblad@cshl.edu.
authors.forename: Mikala
authors.initials: M
authors.lastname: Egeblad
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000096:biosynthesis*; D053208:Kaplan-Meier Estimate; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D027601:Polyomavirus Infections; D040081:Protein Array Analysis; D012192:Retroviridae Infections; D013539:Simian virus 40; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D014412:Tumor Virus Infections
chemical_list: D000957:Antigens, Viral, Tumor; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9