Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species.
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.
O'Brien
Jenean
J
Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Mail Stop 8117, RC-1 S, 8401K, 12801 E. 17 Avenue, UCD, Aurora, CO 80045, USA.
Lyons
Traci
T
Monks
Jenifer
J
Lucia
M Scott
MS
Wilson
R Storey
RS
Hines
Lisa
L
Man
Yan-gao
YG
Borges
Virginia
V
Schedin
Pepper
P
D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010641:Phenotype; D049590:Postpartum Period / Q000276:immunology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014886:Weaning
D015415:Biomarkers; D003094:Collagen; D020782:Matrix Metalloproteinases