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

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.

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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

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Acknowledgments

The authors would like to acknowledge the help of Colin Monks and Ben FranzDale (Intelligent Imaging Innovations, Inc.) for 3D imaging/spherical aberration correction, and for ray-trace, volumetric rendering, respectively. We would like to thank Dr. H. Shelton Earp III for letting us preview the MerTK manuscript. The authors would like to extend sincere apologies to any colleagues whose work we missed.

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Correspondence to Jenifer Monks.

Electronic Supplementary Material

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10911_2009_9121_MOESM1_ESM.mov

Mammary 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

Volumetric rendering of the data in A, after constrained iterative deconvolution. Shown is rotation from −30 to 210 degrees (MOV 9.94 mb)

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)

Fig. S1 Movie 1

Mammary 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)

Fig. S1 Movie 2

Volumetric rendering of the data in A, after constrained iterative deconvolution. Shown is rotation from −30 to 210 degrees (MOV 9.94 mb)

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Monks, J., Henson, P.M. Differentiation of the Mammary Epithelial Cell during Involution: Implications for Breast Cancer. J Mammary Gland Biol Neoplasia 14, 159–170 (2009). https://doi.org/10.1007/s10911-009-9121-0

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Keywords

  • Mammary involution
  • Metastatic breast cancer