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
Article

Abstract

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.

Keywords

Macrophages Immunotherapy Microenvironment Chemoprevention 

Abbreviations

ATP

adenosine triphosphate

arg-1

arginase 1

AMP

adenosine monophosphate

BMI

body mass index

CCL

chemokine (C-C motif) ligand

CD

cluster of differentiation

CK

cytokeratin

COX-2

cyclooxygenase-2

CSF-1

colony stimulating factor-1

CSF-1R

colony stimulating factor-1 receptor

CTLA-4

cytotoxic T-lymphocyte antigen 4

CXCL

chemoattractant chemokine (C-X-C motif) ligand

ECM

extracellular matrix

EGF

epidermal growth factor

FDA

Food and Drug Administration

FGF

fibroblast growth factor

GM-CSF

granulocyte-macrophage colony-stimulating factor

ICE

interleukin-1β converting enzyme

IFNγ

interferon gamma

IL

interleukin

iNOS

inducible nitric oxide synthase

Inv

Involution

Lac

lactation

LBP

lipopolysaccharide binding protein

LRP1

low density lipoprotein-related protein 1

LPC

lysophosphatidylcholine

LPS

lipopolysaccharide

MCP-1

monocyte chemoattractant protein 12

MHC

major histocompatibility complex

MMPs

matrix metalloproteinases

MMTV

mouse mammary tumor virus

MSC

myeloid suppressor cell

NK

natural killer

NOD

non-obese diabetic

NSAIDs

non-steroidal anti-inflammatory drugs

PD-L1

programmed death ligand 1

PD-1

programmed cell death protein 1

PGE2

prostaglandin E2

Preg

Pregnant

PyMT

polyoma virus middle T antigen

Reg

Regressed

SCID

severe combined immunodeficiency

STAT3

signal transducer and activator of transcription 3

TGF-β

transforming growth factor beta

TNFα

tumor necrosis factor alpha

Treg

regulatory T cell

uPA

urokinase-type plasminogen activator

UTP

uridine-5’-triphosphate

VEGF

vascular endothelial growth factor

Vir

Virgin

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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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