Mammary Gland Involution as an Immunotherapeutic Target for Postpartum Breast Cancer

  • Jaime Fornetti
  • Holly A. Martinson
  • Courtney B. Betts
  • Traci R. Lyons
  • Sonali Jindal
  • Qiuchen Guo
  • Lisa M. Coussens
  • Virginia F. Borges
  • Pepper Schedin


Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined ‘hot-spot’ of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment.


Macrophages Immunotherapy Microenvironment Chemoprevention 



adenosine triphosphate


arginase 1


adenosine monophosphate


body mass index


chemokine (C-C motif) ligand


cluster of differentiation






colony stimulating factor-1


colony stimulating factor-1 receptor


cytotoxic T-lymphocyte antigen 4


chemoattractant chemokine (C-X-C motif) ligand


extracellular matrix


epidermal growth factor


Food and Drug Administration


fibroblast growth factor


granulocyte-macrophage colony-stimulating factor


interleukin-1β converting enzyme


interferon gamma




inducible nitric oxide synthase






lipopolysaccharide binding protein


low density lipoprotein-related protein 1






monocyte chemoattractant protein 12


major histocompatibility complex


matrix metalloproteinases


mouse mammary tumor virus


myeloid suppressor cell


natural killer


non-obese diabetic


non-steroidal anti-inflammatory drugs


programmed death ligand 1


programmed cell death protein 1


prostaglandin E2




polyoma virus middle T antigen




severe combined immunodeficiency


signal transducer and activator of transcription 3


transforming growth factor beta


tumor necrosis factor alpha


regulatory T cell


urokinase-type plasminogen activator




vascular endothelial growth factor




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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jaime Fornetti
    • 1
    • 2
    • 3
  • Holly A. Martinson
    • 1
    • 2
    • 4
  • Courtney B. Betts
    • 1
    • 2
    • 5
  • Traci R. Lyons
    • 1
    • 2
  • Sonali Jindal
    • 1
    • 2
  • Qiuchen Guo
    • 1
    • 2
    • 4
  • Lisa M. Coussens
    • 6
  • Virginia F. Borges
    • 1
    • 2
  • Pepper Schedin
    • 1
    • 2
    • 3
    • 4
    • 5
    • 6
  1. 1.Department of Medicine, Division of Medical OncologyUniversity of Colorado Anschutz Medical CampusAuroraUSA
  2. 2.Young Women’s Breast Cancer Translational Program, University of Colorado Cancer CenterUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.Program in Reproductive SciencesUniversity of Colorado Anschutz Medical CampusAuroraUSA
  4. 4.Cancer Biology ProgramUniversity of Colorado Anschutz Medical CampusAuroraUSA
  5. 5.Cell Biology, Stem cells, and DevelopmentAuroraUSA
  6. 6.Department of Cell & Developmental Biology, Knight Cancer InstituteOregon Health & Science UniversityPortlandUSA

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