title: Efferocytosis produces a prometastatic landscape during postpartum mammary gland involution.
abstract: Breast cancers that occur in women 2-5 years postpartum are more frequently diagnosed at metastatic stages and correlate with poorer outcomes compared with breast cancers diagnosed in young, premenopausal women. The molecular mechanisms underlying the malignant severity associated with postpartum breast cancers (ppBCs) are unclear but relate to stromal wound-healing events during postpartum involution, a dynamic process characterized by widespread cell death in milk-producing mammary epithelial cells (MECs). Using both spontaneous and allografted mammary tumors in fully immune-competent mice, we discovered that postpartum involution increases mammary tumor metastasis. Cell death was widespread, not only occurring in MECs but also in tumor epithelium. Dying tumor cells were cleared through receptor tyrosine kinase MerTK-dependent efferocytosis, which robustly induced the transcription of genes encoding wound-healing cytokines, including IL-4, IL-10, IL-13, and TGF-β. Animals lacking MerTK and animals treated with a MerTK inhibitor exhibited impaired efferocytosis in postpartum tumors, a reduction of M2-like macrophages but no change in total macrophage levels, decreased TGF-β expression, and a reduction of postpartum tumor metastasis that was similar to the metastasis frequencies observed in nulliparous mice. Moreover, TGF-β blockade reduced postpartum tumor metastasis. These data suggest that widespread cell death during postpartum involution triggers efferocytosis-induced wound-healing cytokines in the tumor microenvironment that promote metastatic tumor progression.
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Stanford
authors.forename: Christian
authors.initials: C
authors.lastname: Young
authors.forename: Donna
authors.initials: D
authors.lastname: Hicks
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.forename: David B
authors.initials: DB
authors.lastname: Vaught
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Morrison
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Lim
authors.forename: Michelle
authors.initials: M
authors.lastname: Williams
authors.forename: Dana M
authors.initials: DM
authors.lastname: Brantley-Sieders
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.forename: Debra
authors.initials: D
authors.lastname: Tonetti
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
mesh_terms: D000818:Animals; D017209:Apoptosis; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D061986:MCF-7 Cells; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology* / Q000503:physiopathology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010587:Phagocytosis; D049590:Postpartum Period; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D015854:Up-Regulation; D000076202:c-Mer Tyrosine Kinase
chemical_list: D016207:Cytokines; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase