title: Neutrophils drive accelerated tumor progression in the collagen-dense mammary tumor microenvironment.
abstract: High mammographic density has been correlated with a 4-fold to 6-fold increased risk of developing breast cancer, and is associated with increased stromal deposition of extracellular matrix proteins, including collagen I. The molecular and cellular mechanisms responsible for high breast tissue density are not completely understood.
  
  
  
  We previously described accelerated tumor formation and metastases in a transgenic mouse model of collagen-dense mammary tumors (type I collagen-α1 (Col1α1)(tm1Jae) and mouse mammary tumor virus - polyoma virus middle T antigen (MMTV-PyVT)) compared to wild-type mice. Using ELISA cytokine arrays and multi-color flow cytometry analysis, we studied cytokine signals and the non-malignant, immune cells in the collagen-dense tumor microenvironment that may promote accelerated tumor progression and metastasis.
  
  
  
  Collagen-dense tumors did not show any alteration in immune cell populations at late stages. The cytokine signals in the mammary tumor microenvironment were clearly different between wild-type and collagen-dense tumors. Cytokines associated with neutrophil signaling, such as granulocyte monocyte-colony stimulated factor (GM-CSF), were increased in collagen-dense tumors. Depleting neutrophils with anti-Ly6G (1A8) significantly reduced the number of tumors, and blocked metastasis in over 80 % of mice with collagen-dense tumors, but did not impact tumor growth or metastasis in wild-type mice.
  
  
  
  Our study suggests that tumor progression in a collagen-dense microenvironment is mechanistically different, with pro-tumor neutrophils, compared to a non-dense microenvironment.
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA.|UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA.|Present Address: Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: María G
authors.initials: MG
authors.lastname: García-Mendoza
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA.|UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Inman
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA.|UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Ponik
authors.affiliation: UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Jeffery
authors.affiliation: UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA.
authors.forename: Dagna S
authors.initials: DS
authors.lastname: Sheerar
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Van Doorn
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin - Madison, Madison, WI, USA. pjkeely@wisc.edu.|UW Carbone Cancer Center, University of Wisconsin - Madison, Madison, WI, USA. pjkeely@wisc.edu.|Wisconsin Institutes of Medical Research, 1111 Highland Ave., Madison, WI, 53705, USA. pjkeely@wisc.edu.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009362:Neoplasm Metastasis; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D049268:Positron-Emission Tomography; D013154:Spleen / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D016207:Cytokines; D003094:Collagen
keywords: Breast cancer; Collagen; Cytokines; Extracellular matrix; MMTV-PyVT; Stroma; Tumor associated neutrophils; Tumor microenvironment