Physiologically activated mammary fibroblasts promote postpartum mammary cancer

Qiuchen Guo, Jessica Minnier, Julja Burchard, Kami Chiotti, Paul Spellman, Pepper Schedin

Research output: Contribution to journalArticle

6 Citations (Scopus)

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, and Cxcl12 genes. 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.

Original languageEnglish (US)
Pages (from-to)e89206
JournalJCI insight
Volume2
Issue number6
DOIs
StatePublished - Mar 23 2017

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Postpartum Period
Breast
Fibroblasts
Breast Neoplasms
Neoplasms
Human Mammary Glands
Immunosuppressive Agents
Monocytes
Cell Death
Protein-Lysine 6-Oxidase
Fibrillar Collagens
T-Lymphocytes
Granzymes
Ibuprofen
Weaning
Dinoprostone
Pregnant Women
Collagen
Parturition
Transplants

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Physiologically activated mammary fibroblasts promote postpartum mammary cancer. / Guo, Qiuchen; Minnier, Jessica; Burchard, Julja; Chiotti, Kami; Spellman, Paul; Schedin, Pepper.

In: JCI insight, Vol. 2, No. 6, 23.03.2017, p. e89206.

Research output: Contribution to journalArticle

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