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Mammary Gland Involution as an Immunotherapeutic Target for Postpartum Breast Cancer

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

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.

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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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  1. Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA

    Jaime Fornetti, Holly A. Martinson, Courtney B. Betts, Traci R. Lyons, Sonali Jindal, Qiuchen Guo, Virginia F. Borges & Pepper Schedin

  2. Young Women’s Breast Cancer Translational Program, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, 1665 Aurora Court, Aurora, CO, 80045, USA

    Jaime Fornetti, Holly A. Martinson, Courtney B. Betts, Traci R. Lyons, Sonali Jindal, Qiuchen Guo, Virginia F. Borges & Pepper Schedin

  3. Program in Reproductive Sciences, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA

    Jaime Fornetti & Pepper Schedin

  4. Cancer Biology Program, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO, 80045, USA

    Holly A. Martinson, Qiuchen Guo & Pepper Schedin

  5. Cell Biology, Stem cells, and Development, 12801 E 17th Ave, Aurora, CO, 80045, USA

    Courtney B. Betts & Pepper Schedin

  6. Department of Cell & Developmental Biology, Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA

    Lisa M. Coussens & Pepper Schedin

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Fornetti, J., Martinson, H.A., Betts, C.B. et al. Mammary Gland Involution as an Immunotherapeutic Target for Postpartum Breast Cancer. J Mammary Gland Biol Neoplasia 19, 213–228 (2014). https://doi.org/10.1007/s10911-014-9322-z

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