title: Physiologically activated mammary fibroblasts promote postpartum mammary cancer.
abstract: Women diagnosed with breast cancer within 5 years of childbirth have poorer prognosis than nulliparous or pregnant women. Weaning-induced breast involution is implicated, as the collagen-rich, immunosuppressive microenvironment of the involuting mammary gland is tumor promotional in mice. To investigate the role of mammary fibroblasts, isolated mammary PDGFRα+cells from nulliparous and postweaning mice were assessed for activation phenotype and protumorigenic function. Fibroblast activation during involution was evident by increased expression of fibrillar collagens, lysyl oxidase,Tgfb1, andCxcl12genes. The ability of mammary tumors to grow in an isogenic, orthotopic transplant model was increased when tumor cells were coinjected with involution-derived compared with nulliparous-derived mammary fibroblasts. Mammary tumors in the involution-fibroblast group had increased Ly6C+monocytes at the tumor border, and decreased CD8+T cell infiltration and tumor cell death. Ibuprofen treatment suppressed involution-fibroblast activation and tumor promotional capacity, concurrent with decreases in tumor Ly6C+monocytes, and increases in intratumoral CD8+T cell infiltration, granzyme levels, and tumor cell death. In total, our data identify a COX/prostaglandin E2 (PGE2)-dependent activated mammary fibroblast within the involuting mammary gland that displays protumorigenic, immunosuppressive activity, identifying fibroblasts as potential targets for the prevention and treatment of postpartum breast cancer.
authors.affiliation: Department of Cell, Developmental and Cancer Biology.
authors.forename: Qiuchen
authors.initials: Q
authors.lastname: Guo
authors.affiliation: School of Public Health.
authors.forename: Jessica
authors.initials: J
authors.lastname: Minnier
authors.affiliation: School of Medicine, Computational Biology.
authors.forename: Julja
authors.initials: J
authors.lastname: Burchard
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Kami
authors.initials: K
authors.lastname: Chiotti
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, USA.|Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Spellman
authors.affiliation: Department of Cell, Developmental and Cancer Biology.|Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.|Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Pepper
authors.initials: P
authors.lastname: Schedin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007052:Ibuprofen / Q000008:administration & dosage; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D049590:Postpartum Period; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020796:Receptor, Platelet-Derived Growth Factor alpha; D007052:Ibuprofen