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


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


ATPase, H + transporting lysosomal (vacuolar proton pump)


AXL receptor tyrosine kinase


brain-specific angiogenesis inhibitor 1


BCL2-associated X protein


B-cell CLL/lymphoma 2


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


BH3 interacting domain death agonist


bone marrow-derived macrophages


bovine mammary epithelial cells


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


monocyte differentiation antigen CD14


sialic acid binding Ig-like lectin 1, sialoadhesin


mannose receptor, C type 1


platelet/endothelial cell adhesion molecule


cluster determinant 36 or thrombospondin receptor


cell surface glycoprotein CD44 (Indian Blood Group)


melanoma 1 antigen


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


cyclin-dependent kinase 4


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


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


eosinophil chemotactic factor-L or chitinase 3-like 3


extracellular matrix


epidermal growth factor


epithelial to mesenchymal transition


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


fetal bovine serum


fibroblast growth factor


growth arrest-specific 6


lymphocyte antigen 6 complex, locus G


human papillomavirus


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


insulin-like growth factor binding protein 5


inducible nitric oxide synthase


involution day 1 or 24 h post-forced-weaning


involution day four


lysosomal-associated membrane protein 2


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




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


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


lymphocyte antigen 6 complex, locus C1

M1 macrophage:

classically activated macrophage

M2 macrophage:

alternatively activated macrophage


complement component receptor 3, alpha or integrin alpha M


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


microtubule-associated protein 1 light chain 3 beta


mitogen-activated protein kinase


mammary epithelial cell


c-mer proto-oncogene tyrosine kinase


milk fat globule-EGF factor 8 protein or lactadherin


matrix metalloproteinase


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


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


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


myeloid differentiation primary response gene (88)


myristoylated Akt


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


Na–Pi type IIb co-transporter


programmed cell death


phosphoinositide 3-kinase


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


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




phosphatase and tensin homolog


recombination-activating gene-1


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


suppressor of cytokine signaling 3


signal transducer and activator of transcription 5


tumor-associated macrophage


transforming growth factor, beta receptor II


transforming growth factor beta


thrombospondin 1


T-cell immunoglobulin and mucin domain containing 4


tissue-inhibitor of metalloproteinase 3


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


tumor necrosis factor


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


TYRO3 protein tyrosine kinase 3


urokinase plasminogen activator


vascular endothelial growth factor


whey acidic protein


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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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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)


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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  • Mammary involution
  • Metastatic breast cancer