Journal of Mammary Gland Biology and Neoplasia

, Volume 14, Issue 2, pp 159–170

Differentiation of the Mammary Epithelial Cell during Involution: Implications for Breast Cancer

Article

DOI: 10.1007/s10911-009-9121-0

Cite this article as:
Monks, J. & Henson, P.M. J Mammary Gland Biol Neoplasia (2009) 14: 159. doi:10.1007/s10911-009-9121-0

Abstract

That milk secretion is not the final differentiated state of the mammary alveolar cells is a relatively new concept. Recent work has suggested that secreting, mammary epithelial cells (MECs) have another function to perform before they undergo cell death in the involuting mammary gland. That is, they help in the final clearance and breakdown of their neighboring cells (and likely residual milk as well.) They become, for a short time, amateur phagocytes, or efferocytes, and then are believed to die and be cleared themselves. Although relatively little study has been made of this change in the functional state of the MEC, nevertheless we may speculate from the involution literature, and extend findings from other systems of apoptotic cell clearance, on some of the mechanisms involved. And with the finding that involution may represent a unique susceptibility window for the progression of metastatic breast cancer, we may suggest areas for future research along these lines as well.

Keywords

Mammary involutionMetastatic breast cancer

Abbreviations

Akt/PKB

v-akt murine thymoma viral oncogene homolog or protein kinase B

ATP6K

ATPase, H + transporting lysosomal (vacuolar proton pump)

Axl

AXL receptor tyrosine kinase

Bai1

brain-specific angiogenesis inhibitor 1

Bax

BCL2-associated X protein

Bcl-2

B-cell CLL/lymphoma 2

Beclin-1/ATG6

coiled-coil, moesin-like BCL2 interacting protein or autophagy related 6 homolog

Bid

BH3 interacting domain death agonist

BMDM

bone marrow-derived macrophages

BMEC

bovine mammary epithelial cells

CD11c/ITGAX

integrin, alpha X (complement component 3 receptor 4 subunit)

CD14

monocyte differentiation antigen CD14

CD169/SIGLEC1

sialic acid binding Ig-like lectin 1, sialoadhesin

CD206/MRC1

mannose receptor, C type 1

CD31/PECAM1

platelet/endothelial cell adhesion molecule

CD36

cluster determinant 36 or thrombospondin receptor

CD44

cell surface glycoprotein CD44 (Indian Blood Group)

CD63a

melanoma 1 antigen

CD68a

macrophage antigen CD68 or macrosialin or scavenger receptor class D, member 1

CDK4

cyclin-dependent kinase 4

Cre

Cre recombinase, a Type I topoisomerase from P1 bacteriophage that catalyzes site-specific recombination of DNA between loxP sites

CSF1R /Csfmr/CD115

macrophage colony stimulating factor I receptor

CXCL10

chemokine (C-X-C motif) ligand 10 or interferon-inducible cytokine IP-10

ECF-L/Ym-1/Chi3l3

eosinophil chemotactic factor-L or chitinase 3-like 3

ECM

extracellular matrix

EGF

epidermal growth factor

EMT

epithelial to mesenchymal transition

F4/80/EMR1

cell surface glycoprotein F4/80 or EGF-like module containing, mucin-like, hormone receptor-like sequence 1

FBS

fetal bovine serum

FGF

fibroblast growth factor

Gas6

growth arrest-specific 6

Gr-1/Ly-6g

lymphocyte antigen 6 complex, locus G

HPV

human papillomavirus

IAP/CD47a

CD47 antigen or Rh-related antigen or integrin-associated signal transducer

IGFBP5

insulin-like growth factor binding protein 5

iNOS/NOS-2

inducible nitric oxide synthase

Invo1

involution day 1 or 24 h post-forced-weaning

Invo4

involution day four

LAMP2

lysosomal-associated membrane protein 2

LGP85/CD36l2/LIMP-2/SCARB2

85 kDa lysosomal sialoglycoprotein scavenger receptor class B, member 2 or (collagen type I receptor, thrombospondin receptor)-like 2 or lysosomal integral membrane protein II or scavenger receptor class B, member 2

LPS

lipopolysaccharide

LRP/CD91/A2MR

low density lipoprotein-related protein or alpha 2-macroglobulin receptor

Ly112/Scara2/MARCO

scavenger receptor class A, member 2 or macrophage receptor with collagenous structure

Ly-6c

lymphocyte antigen 6 complex, locus C1

M1 macrophage

classically activated macrophage

M2 macrophage

alternatively activated macrophage

Mac-1/CD11b/CR3/Ly-40/Itgam

complement component receptor 3, alpha or integrin alpha M

Mac2/galectin-3/LGALS3

lectin, galactoside-binding, soluble, 3 or IgE-binding protein or laminin-binding protein

Map1lc3

microtubule-associated protein 1 light chain 3 beta

MAPK

mitogen-activated protein kinase

MEC

mammary epithelial cell

MerTK

c-mer proto-oncogene tyrosine kinase

MFG-E8

milk fat globule-EGF factor 8 protein or lactadherin

MMP

matrix metalloproteinase

MMTV-Neu

expression of the Neu oncogene (HER2/ErbB2) using the mouse mammary tumor virus LTR promoter

MMTV-Wnt

the protooncogene, wingless-related MMTV integration site 1, expressed using the mouse mammary tumor virus LTR promoter

mTOR/FRAP1

mammalian target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1

MyD88

myeloid differentiation primary response gene (88)

Myr-Akt

myristoylated Akt

NF-κB

nuclear factor of kappa light polypeptide gene enhancer in B-cells

Npt2b

Na–Pi type IIb co-transporter

PCD

programmed cell death

PI3K

phosphoinositide 3-kinase

PiMEC

parity-identified mammary epithelial cell (previously parity-induced)

ProS1

protein S, alpha or vitamin K-dependent plasma protein S

PtdSer

phosphatidylserine

PTEN

phosphatase and tensin homolog

RAG-1

recombination-activating gene-1

ROSA-LacZ

reporter transgene utilizing a floxed transcriptional Stop sequence between the Rosa promoter and the beta-galactosidase (LacZ) coding sequence

SOCS3

suppressor of cytokine signaling 3

Stat5

signal transducer and activator of transcription 5

TAM

tumor-associated macrophage

TβRII

transforming growth factor, beta receptor II

TGFβ

transforming growth factor beta

Thbs1

thrombospondin 1

Tim4

T-cell immunoglobulin and mucin domain containing 4

TIMP3

tissue-inhibitor of metalloproteinase 3

TMEM4/CNPY2

MIR-interacting saposin-like protein or canopy 2 homolog or transmembrane protein 4

TNF

tumor necrosis factor

TWEAK/Tnfsf12

tumor necrosis factor-like weak inducer of apoptosis or tumor necrosis factor (ligand) superfamily, member 12

Tyro3

TYRO3 protein tyrosine kinase 3

UPA

urokinase plasminogen activator

VEGF

vascular endothelial growth factor

WAP

whey acidic protein

Supplementary material

10911_2009_9121_MOESM1_ESM.mov (5 mb)
Fig. S1 Movie 1Mammary gland collected at day 1.5 post-wean, frozen section stained with M30 cytodeath (shown in green), phalloidin (red) and Hoechst (blue). 149 planes, at a spacing of 0.2 microns were collected. The movie shows every other optical section of collected data (MOV 4.95 mb)
10911_2009_9121_MOESM2_ESM.mov (10 mb)
Fig. S1 Movie 2Volumetric rendering of the data in A, after constrained iterative deconvolution. Shown is rotation from −30 to 210 degrees (MOV 9.94 mb)
View video
Fig. S1 Movie 3

Movie showing a rotation of dynamically lit, ray-trace, volumetric rendering of deconvolved mammary gland data. Phalloidin staining is shown at 88% opacity to allow viewing of internal structures. The angle of the light source is shown by the arrow in the top right, and the angle of viewing is shown by the axes in the lower left. Acknowledgment: Ben FranzDale, Intelligent Imaging Innovations, for ray-trace, volumetric rendering (MOV 4.64 mb)

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Webb Waring CenterUniversity of Colorado, Denver, Anschutz Medical CampusAuroraUSA
  2. 2.National Jewish HealthDenverUSA