Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species

Jenean O'Brien, Traci Lyons, Jenifer Monks, M. Scott Lucia, R. Storey Wilson, Lisa Hines, Yan Gao Man, Virginia Borges, Pepper Schedin

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Recent pregnancy correlates with decreased survival for breast cancer patients compared with non-pregnancy-associated breast cancer. We hypothesize that postpartum mammary involution induces metastasis through wound-healing programs known to promote cancer. It is unknown whether alternatively activated M2 macrophages, immune cells important in wound-healing and experimental tumorigenesis that also predict poor prognosis for breast cancer patients, are recruited to the normal involuting gland. Macrophage markers CD68, CSF-1R, and F4/80 were examined across the pregnancy and involution cycle in rodent and human mammary tissues. Quantitative immunohistochemistry revealed up to an eightfold increase in macrophage number during involution, which returned to nulliparous levels with full regression. The involution macrophages exhibit an M2 phenotype as determined by high arginase-1 and low inducible nitric oxide synthase staining in rodent tissue, and by mannose receptor expression in human breast tissue. M2 cytokines IL-4 and IL-13 also peaked during involution. Extracellular matrix (ECM) isolated from involuting rat mammary glands was chemotactic for macrophages compared with nulliparous mammary ECM. Fibrillar collagen levels and proteolysis increased dramatically during involution, and denatured collagen I acted as a strong chemoattractant for macrophages in cell culture, suggesting proteolyzed fibrillar collagen as a candidate ECM mediator of macrophage recruitment. M2 macrophages, IL-4, IL-13, fibrillar collagen accumulation, and proteolysis of collagen are all components of tumor promotional microenvironments, and thus may mediate promotion of breast cancers arising in the postpartum setting.

Original languageEnglish (US)
Pages (from-to)1241-1255
Number of pages15
JournalAmerican Journal of Pathology
Volume176
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

Fingerprint

Human Mammary Glands
Postpartum Period
Collagen
Macrophages
Fibrillar Collagens
Breast
Breast Neoplasms
Extracellular Matrix
Interleukin-13
Interleukin-4
Wound Healing
Proteolysis
Rodentia
Arginase
Pregnancy
Tumor Microenvironment
Chemotactic Factors
Nitric Oxide Synthase Type II
Carcinogenesis
Cell Culture Techniques

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. / O'Brien, Jenean; Lyons, Traci; Monks, Jenifer; Lucia, M. Scott; Wilson, R. Storey; Hines, Lisa; Man, Yan Gao; Borges, Virginia; Schedin, Pepper.

In: American Journal of Pathology, Vol. 176, No. 3, 03.2010, p. 1241-1255.

Research output: Contribution to journalArticle

O'Brien, Jenean ; Lyons, Traci ; Monks, Jenifer ; Lucia, M. Scott ; Wilson, R. Storey ; Hines, Lisa ; Man, Yan Gao ; Borges, Virginia ; Schedin, Pepper. / Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. In: American Journal of Pathology. 2010 ; Vol. 176, No. 3. pp. 1241-1255.
@article{12695bf7ec294ea7a430268df43da095,
title = "Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species",
abstract = "Recent pregnancy correlates with decreased survival for breast cancer patients compared with non-pregnancy-associated breast cancer. We hypothesize that postpartum mammary involution induces metastasis through wound-healing programs known to promote cancer. It is unknown whether alternatively activated M2 macrophages, immune cells important in wound-healing and experimental tumorigenesis that also predict poor prognosis for breast cancer patients, are recruited to the normal involuting gland. Macrophage markers CD68, CSF-1R, and F4/80 were examined across the pregnancy and involution cycle in rodent and human mammary tissues. Quantitative immunohistochemistry revealed up to an eightfold increase in macrophage number during involution, which returned to nulliparous levels with full regression. The involution macrophages exhibit an M2 phenotype as determined by high arginase-1 and low inducible nitric oxide synthase staining in rodent tissue, and by mannose receptor expression in human breast tissue. M2 cytokines IL-4 and IL-13 also peaked during involution. Extracellular matrix (ECM) isolated from involuting rat mammary glands was chemotactic for macrophages compared with nulliparous mammary ECM. Fibrillar collagen levels and proteolysis increased dramatically during involution, and denatured collagen I acted as a strong chemoattractant for macrophages in cell culture, suggesting proteolyzed fibrillar collagen as a candidate ECM mediator of macrophage recruitment. M2 macrophages, IL-4, IL-13, fibrillar collagen accumulation, and proteolysis of collagen are all components of tumor promotional microenvironments, and thus may mediate promotion of breast cancers arising in the postpartum setting.",
author = "Jenean O'Brien and Traci Lyons and Jenifer Monks and Lucia, {M. Scott} and Wilson, {R. Storey} and Lisa Hines and Man, {Yan Gao} and Virginia Borges and Pepper Schedin",
year = "2010",
month = "3",
doi = "10.2353/ajpath.2010.090735",
language = "English (US)",
volume = "176",
pages = "1241--1255",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species

AU - O'Brien, Jenean

AU - Lyons, Traci

AU - Monks, Jenifer

AU - Lucia, M. Scott

AU - Wilson, R. Storey

AU - Hines, Lisa

AU - Man, Yan Gao

AU - Borges, Virginia

AU - Schedin, Pepper

PY - 2010/3

Y1 - 2010/3

N2 - Recent pregnancy correlates with decreased survival for breast cancer patients compared with non-pregnancy-associated breast cancer. We hypothesize that postpartum mammary involution induces metastasis through wound-healing programs known to promote cancer. It is unknown whether alternatively activated M2 macrophages, immune cells important in wound-healing and experimental tumorigenesis that also predict poor prognosis for breast cancer patients, are recruited to the normal involuting gland. Macrophage markers CD68, CSF-1R, and F4/80 were examined across the pregnancy and involution cycle in rodent and human mammary tissues. Quantitative immunohistochemistry revealed up to an eightfold increase in macrophage number during involution, which returned to nulliparous levels with full regression. The involution macrophages exhibit an M2 phenotype as determined by high arginase-1 and low inducible nitric oxide synthase staining in rodent tissue, and by mannose receptor expression in human breast tissue. M2 cytokines IL-4 and IL-13 also peaked during involution. Extracellular matrix (ECM) isolated from involuting rat mammary glands was chemotactic for macrophages compared with nulliparous mammary ECM. Fibrillar collagen levels and proteolysis increased dramatically during involution, and denatured collagen I acted as a strong chemoattractant for macrophages in cell culture, suggesting proteolyzed fibrillar collagen as a candidate ECM mediator of macrophage recruitment. M2 macrophages, IL-4, IL-13, fibrillar collagen accumulation, and proteolysis of collagen are all components of tumor promotional microenvironments, and thus may mediate promotion of breast cancers arising in the postpartum setting.

AB - Recent pregnancy correlates with decreased survival for breast cancer patients compared with non-pregnancy-associated breast cancer. We hypothesize that postpartum mammary involution induces metastasis through wound-healing programs known to promote cancer. It is unknown whether alternatively activated M2 macrophages, immune cells important in wound-healing and experimental tumorigenesis that also predict poor prognosis for breast cancer patients, are recruited to the normal involuting gland. Macrophage markers CD68, CSF-1R, and F4/80 were examined across the pregnancy and involution cycle in rodent and human mammary tissues. Quantitative immunohistochemistry revealed up to an eightfold increase in macrophage number during involution, which returned to nulliparous levels with full regression. The involution macrophages exhibit an M2 phenotype as determined by high arginase-1 and low inducible nitric oxide synthase staining in rodent tissue, and by mannose receptor expression in human breast tissue. M2 cytokines IL-4 and IL-13 also peaked during involution. Extracellular matrix (ECM) isolated from involuting rat mammary glands was chemotactic for macrophages compared with nulliparous mammary ECM. Fibrillar collagen levels and proteolysis increased dramatically during involution, and denatured collagen I acted as a strong chemoattractant for macrophages in cell culture, suggesting proteolyzed fibrillar collagen as a candidate ECM mediator of macrophage recruitment. M2 macrophages, IL-4, IL-13, fibrillar collagen accumulation, and proteolysis of collagen are all components of tumor promotional microenvironments, and thus may mediate promotion of breast cancers arising in the postpartum setting.

UR - http://www.scopus.com/inward/record.url?scp=77749264278&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77749264278&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2010.090735

DO - 10.2353/ajpath.2010.090735

M3 - Article

VL - 176

SP - 1241

EP - 1255

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 3

ER -