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

Article

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 involution Metastatic 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)
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)

References

  1. 1.
    D'Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB, et al. Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol. 2002;16(9):2034–51. doi:10.1210/me.2002-0073.PubMedCrossRefGoogle Scholar
  2. 2.
    Balogh GA, Heulings R, Mailo DA, Russo PA, Sheriff F, Russo IH, et al. Genomic signature induced by pregnancy in the human breast. Int J Oncol. 2006;28(2):399–410.PubMedGoogle Scholar
  3. 3.
    Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6(4):281–91. doi:10.1038/nrc1839.PubMedCrossRefGoogle Scholar
  4. 4.
    Maroulakou IG, Oemler W, Naber SP, Klebba I, Kuperwasser C, Tsichlis PN. Distinct roles of the three Akt isoforms in lactogenic differentiation and involution. J Cell Physiol. 2008;217(2):468–77. doi:10.1002/jcp.21518.PubMedCrossRefGoogle Scholar
  5. 5.
    Cabodi S, Tinnirello A, Di Stefano P, Bisaro B, Ambrosino E, Castellano I, et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 2006;66(9):4672–80. doi:10.1158/0008-5472.CAN-05-2909.PubMedCrossRefGoogle Scholar
  6. 6.
    Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, et al. Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene. 2006;25(24):3408–23. doi:10.1038/sj.onc.1208964.PubMedCrossRefGoogle Scholar
  7. 7.
    Abell K, Bilancio A, Clarkson RW, Tiffen PG, Altaparmakov AI, Burdon TG, et al. Stat3-induced apoptosis requires a molecular switch in PI(3) K subunit composition. Nat Cell Biol. 2005;7(4):392–8. doi:10.1038/ncb1242.PubMedCrossRefGoogle Scholar
  8. 8.
    Schwertfeger KL, McManaman JL, Palmer CA, Neville MC, Anderson SM. Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation. J Lipid Res. 2003;44(6):1100–12. doi:10.1194/jlr.M300045-JLR200.PubMedCrossRefGoogle Scholar
  9. 9.
    Moorehead RA, Fata JE, Johnson MB, Khokha R. Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice. Cell Death Differ. 2001;8(1):16–29. doi:10.1038/sj.cdd.4400762.PubMedCrossRefGoogle Scholar
  10. 10.
    Renner O, Blanco-Aparicio C, Grassow M, Canamero M, Leal JF, Carnero A. Activation of phosphatidylinositol 3-kinase by membrane localization of p110alpha predisposes mammary glands to neoplastic transformation. Cancer Res. 2008;68(23):9643–53. doi:10.1158/0008-5472.CAN-08-1539.PubMedCrossRefGoogle Scholar
  11. 11.
    Sharp JA, Lefevre C, Brennan AJ, Nicholas KR. The fur seal-a model lactation phenotype to explore molecular factors involved in the initiation of apoptosis at involution. J Mammary Gland Biol Neoplasia. 2007;12(1):47–58. doi:10.1007/s10911-007-9037-5.PubMedCrossRefGoogle Scholar
  12. 12.
    Lemay DG, Neville MC, Rudolph MC, Pollard KS, German JB. Gene regulatory networks in lactation: identification of global principles using bioinformatics. BMC Syst Biol. 2007;1:56. doi:10.1186/1752-0509-1-56.PubMedCrossRefGoogle Scholar
  13. 13.
    Sutherland KD, Lindeman GJ, Visvader JE. The molecular culprits underlying precocious mammary gland involution. J Mammary Gland Biol Neoplasia. 2007;12(1):15–23. doi:10.1007/s10911-007-9034-8.PubMedCrossRefGoogle Scholar
  14. 14.
    Stein T, Salomonis N, Gusterson BA. Mammary gland involution as a multi-step process. J Mammary Gland Biol Neoplasia. 2007;12(1):25–35. doi:10.1007/s10911-007-9035-7.PubMedCrossRefGoogle Scholar
  15. 15.
    Baxter FO, Neoh K, Tevendale MC. The beginning of the end: death signaling in early involution. J Mammary Gland Biol Neoplasia. 2007;12(1):3–13. doi:10.1007/s10911-007-9033-9.PubMedCrossRefGoogle Scholar
  16. 16.
    Monks J, Smith-Steinhart C, Kruk ER, Fadok VA, Henson PM. Epithelial cells remove apoptotic epithelial cells during post-lactation involution of the mouse mammary gland. Biol Reprod. 2008;78(4):586–94. doi:10.1095/biolreprod.107.065045.PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenblatt J, Raff MC, Cramer LP. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol. 2001;11(23):1847–57. doi:10.1016/S0960-9822(01)00587-5.PubMedCrossRefGoogle Scholar
  18. 18.
    Erwig LP, Henson PM. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 2008;15(2):243–50. doi:10.1038/sj.cdd.4402184.PubMedCrossRefGoogle Scholar
  19. 19.
    Monks J, Rosner D, Geske FJ, Lehman L, Hanson L, Neville MC, et al. Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release. Cell Death Differ. 2005;12(2):107–14. doi:10.1038/sj.cdd.4401517.PubMedCrossRefGoogle Scholar
  20. 20.
    Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP, Henson PM. Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem. 2006;281(50):38376–84. doi:10.1074/jbc.M605146200.PubMedCrossRefGoogle Scholar
  21. 21.
    Andrechek ER, Mori S, Rempel RE, Chang JT, Nevins JR. Patterns of cell signaling pathway activation that characterize mammary development. Development. 2008;135(14):2403–13. doi:10.1242/dev.019018.PubMedCrossRefGoogle Scholar
  22. 22.
    Tiffen PG, Omidvar N, Marquez-Almuina N, Croston D, Watson CJ, Clarkson RW. A dual role for oncostatin M signaling in the differentiation and death of mammary epithelial cells in vivo. Mol Endocrinol. 2008;22(12):2677–88. doi:10.1210/me.2008-0097.PubMedCrossRefGoogle Scholar
  23. 23.
    Rudolph MC, McManaman JL, Hunter L, Phang T, Neville MC. Functional development of the mammary gland: use of expression profiling and trajectory clustering to reveal changes in gene expression during pregnancy, lactation, and involution. J Mammary Gland Biol Neoplasia. 2003;8(3):287–307. doi:10.1023/B:JOMG.0000010030.73983.57.PubMedCrossRefGoogle Scholar
  24. 24.
    Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 2004;6(2):R75–91. doi:10.1186/bcr753.PubMedCrossRefGoogle Scholar
  25. 25.
    Bratton DL, Henson PM. Apoptotic cell recognition: will the real phosphatidylserine receptor(s) please stand up? Curr Biol. 2008;18(2):R76–9. doi:10.1016/j.cub.2007.11.024.PubMedCrossRefGoogle Scholar
  26. 26.
    Nakatani H, Aoki N, Nakagawa Y, Jin-No S, Aoyama K, Oshima K, et al. Weaning-induced expression of a milk-fat globule protein, MFG-E8, in mouse mammary glands, as demonstrated by the analyses of its mRNA, protein and phosphatidylserine-binding activity. Biochem J. 2006;395(1):21–30. doi:10.1042/BJ20051459.PubMedCrossRefGoogle Scholar
  27. 27.
    Oshima K, Aoki N, Negi M, Kishi M, Kitajima K, Matsuda T. Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. Biochem Biophys Res Commun. 1999;254(3):522–8. doi:10.1006/bbrc.1998.0107.PubMedCrossRefGoogle Scholar
  28. 28.
    Erwig LP, McPhilips KA, Wynes MW, Ivetic A, Ridley AJ, Henson PM. Differential regulation of phagosome maturation in macrophages and dendritic cells mediated by Rho GTPases and ezrin-radixin-moesin (ERM) proteins. Proc Natl Acad Sci USA. 2006;103(34):12825–30. doi:10.1073/pnas.0605331103.PubMedCrossRefGoogle Scholar
  29. 29.
    Green KA, Lund LR. ECM degrading proteases and tissue remodelling in the mammary gland. Bioessays. 2005;27(9):894–903. doi:10.1002/bies.20281.PubMedCrossRefGoogle Scholar
  30. 30.
    Hu L, Roth JM, Brooks P, Luty J, Karpatkin S. Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Res. 2008;68(12):4666–73. doi:10.1158/0008-5472.CAN-07-6276.PubMedCrossRefGoogle Scholar
  31. 31.
    Castino R, Delpal S, Bouguyon E, Demoz M, Isidoro C, Ollivier-Bousquet M. Prolactin promotes the secretion of active cathepsin D at the basal side of rat mammary acini. Endocrinology. 2008;149(8):4095–105. doi:10.1210/en.2008-0249.PubMedCrossRefGoogle Scholar
  32. 32.
    Berchem G, Glondu M, Gleizes M, Brouillet JP, Vignon F, Garcia M, et al. Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene. 2002;21(38):5951–5. doi:10.1038/sj.onc.1205745.PubMedCrossRefGoogle Scholar
  33. 33.
    Khalkhali-Ellis Z, Hendrix MJ. Elucidating the function of secreted maspin: inhibiting cathepsin D-mediated matrix degradation. Cancer Res. 2007;67(8):3535–9. doi:10.1158/0008-5472.CAN-06-4767.PubMedCrossRefGoogle Scholar
  34. 34.
    Lamparska-Przybysz M, Gajkowska B, Motyl T. Cathepsins and BID are involved in the molecular switch between apoptosis and autophagy in breast cancer MCF-7 cells exposed to camptothecin. J Physiol Pharmacol. 2005;56(Suppl 3):159–79.PubMedGoogle Scholar
  35. 35.
    Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, et al. Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett. 2006;237(2):167–79. doi:10.1016/j.canlet.2005.06.007.PubMedCrossRefGoogle Scholar
  36. 36.
    Motyl T, Gajkowska B, Zarzynska J, Gajewska M, Lamparska-Przybysz M. Apoptosis and autophagy in mammary gland remodeling and breast cancer chemotherapy. J Physiol Pharmacol. 2006;57(Suppl 7):17–32.PubMedGoogle Scholar
  37. 37.
    Atabai K, Sheppard D, Werb Z. Roles of the innate immune system in mammary gland remodeling during involution. J Mammary Gland Biol Neoplasia. 2007;12(1):37–45. doi:10.1007/s10911-007-9036-6.PubMedCrossRefGoogle Scholar
  38. 38.
    Motyl T, Gajewska M, Zarzynska J, Sobolewska A, Gajkowska B. Regulation of autophagy in bovine mammary epithelial cells. Autophagy. 2007;3(5):484–6.PubMedGoogle Scholar
  39. 39.
    Capuco AV, Li M, Long E, Ren S, Hruska KS, Schorr K, et al. Concurrent pregnancy retards mammary involution: effects on apoptosis and proliferation of the mammary epithelium after forced weaning of mice. Biol Reprod. 2002;66(5):1471–6. doi:10.1095/biolreprod66.5.1471.PubMedCrossRefGoogle Scholar
  40. 40.
    Sobolewska A, Gajewska M, Zarzynska J, Gajkowska B, Motyl T. IGF-I, EGF, and sex steroids regulate autophagy in bovine mammary epithelial cells via the mTOR pathway. Eur J Cell Biol. 2009;88(2):117–30. doi:10.1016/j.ejcb.2008.09.004.PubMedCrossRefGoogle Scholar
  41. 41.
    Reinhardt TA, Lippolis JD. Mammary gland involution is associated with rapid down regulation of major mammary Ca2 + -ATPases. Biochem Biophys Res Commun. 2009;378(1):99–102. doi:10.1016/j.bbrc.2008.11.004.PubMedCrossRefGoogle Scholar
  42. 42.
    Fadeel B, Orrenius S. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Intern Med. 2005;258(6):479–517. doi:10.1111/j.1365-2796.2005.01570.x.PubMedCrossRefGoogle Scholar
  43. 43.
    Zheng J, Watson AD, Kerr DE. Genome-wide expression analysis of lipopolysaccharide-induced mastitis in a mouse model. Infect Immun. 2006;74(3):1907–15. doi:10.1128/IAI.74.3.1907-1915.2006.PubMedCrossRefGoogle Scholar
  44. 44.
    Zaragoza R, Miralles VJ, Rus AD, Garcia C, Carmena R, Garcia-Trevijano ER, et al. Weaning induces NOS-2 expression through NF-kappaB modulation in the lactating mammary gland: importance of GSH. Biochem J. 2005;391(Pt 3):581–8. doi:10.1042/BJ20050507.PubMedGoogle Scholar
  45. 45.
    Brown BN, Valentin JE, Stewart-Akers AM, McCabe GP, Badylak SF. Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials. 2009;30(8):1482–91. doi:10.1016/j.biomaterials.2008.11.040.PubMedCrossRefGoogle Scholar
  46. 46.
    Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006;124(2):263–6. doi:10.1016/j.cell.2006.01.007.PubMedCrossRefGoogle Scholar
  47. 47.
    Lewis CE, Pollard JW. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 2006;66(2):605–12. doi:10.1158/0008-5472.CAN-05-4005.PubMedCrossRefGoogle Scholar
  48. 48.
    Sica A, Allavena P, Mantovani A. Cancer related inflammation: the macrophage connection. Cancer Lett. 2008;267(2):204–15. doi:10.1016/j.canlet.2008.03.028.PubMedCrossRefGoogle Scholar
  49. 49.
    Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18(5):349–55. doi:10.1016/j.semcancer.2008.03.004.PubMedCrossRefGoogle Scholar
  50. 50.
    Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev. 2008;222:155–61. doi:10.1111/j.1600-065X.2008.00607.x.PubMedCrossRefGoogle Scholar
  51. 51.
    Hagemann T, Robinson SC, Schulz M, Trumper L, Balkwill FR, Binder C. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 2004;25(8):1543–9. doi:10.1093/carcin/bgh146.PubMedCrossRefGoogle Scholar
  52. 52.
    Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol. 2008;84(3):623–30. doi:10.1189/jlb.1107762.PubMedCrossRefGoogle Scholar
  53. 53.
    Hagemann T, Lawrence T, McNeish I, Charles KA, Kulbe H, Thompson RG, et al. "Re-educating" tumor-associated macrophages by targeting NF-kappaB. J Exp Med. 2008;205(6):1261–8. doi:10.1084/jem.20080108.PubMedCrossRefGoogle Scholar
  54. 54.
    Sutherland KD, Vaillant F, Alexander WS, Wintermantel TM, Forrest NC, Holroyd SL, et al. c-myc as a mediator of accelerated apoptosis and involution in mammary glands lacking Socs3. EMBO J. 2006;25(24):5805–15. doi:10.1038/sj.emboj.7601455.PubMedCrossRefGoogle Scholar
  55. 55.
    Ning Y, Hoang B, Schuller AG, Cominski TP, Hsu MS, Wood TL, et al. Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene. Endocrinology. 2007;148(5):2138–47. doi:10.1210/en.2006-0041.PubMedCrossRefGoogle Scholar
  56. 56.
    Fata JE, Leco KJ, Voura EB, Yu HY, Waterhouse P, Murphy G, et al. Accelerated apoptosis in the Timp-3-deficient mammary gland. J Clin Invest. 2001;108(6):831–41.PubMedGoogle Scholar
  57. 57.
    Schwertfeger KL, Richert MM, Anderson SM. Mammary gland involution is delayed by activated Akt in transgenic mice. Mol Endocrinol. 2001;15(6):867–81. doi:10.1210/me.15.6.867.PubMedCrossRefGoogle Scholar
  58. 58.
    Atabai K, Fernandez R, Huang X, Ueki I, Kline A, Li Y, et al. Mfge8 is critical for mammary gland remodeling during involution. Mol Biol Cell. 2005;16(12):5528–37. doi:10.1091/mbc.E05-02-0128.PubMedCrossRefGoogle Scholar
  59. 59.
    Hanayama R, Nagata S. Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci USA. 2005;102(46):16886–91. doi:10.1073/pnas.0508599102.PubMedCrossRefGoogle Scholar
  60. 60.
    Muraoka-Cook RS, Sandah M, Hunter DM, Strunk KE, Williams JC, Matsushima GK, Graham DK, Earp HS III. Stromal and epithelial expression of MerTK, but not Axl or Tyro3, regulates apoptotic cell clearance and prevents premalignant changes in the mammary epithelium. in press 2009.Google Scholar
  61. 61.
    Raymond A, Ensslin MA, Shur BD. SED1/MFG-E8: A Bi-Motif protein that orchestrates diverse cellular interactions. J Cell Biochem. 2009;106(6):957–66. doi:10.1002/jcb.22076.PubMedCrossRefGoogle Scholar
  62. 62.
    Toth B, Garabuczi E, Sarang Z, Vereb G, Vamosi G, Aeschlimann D, et al. Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells. J Immunol. 2009;182(4):2084–92. doi:10.4049/jimmunol.0803444.PubMedCrossRefGoogle Scholar
  63. 63.
    Bu HF, Zuo XL, Wang X, Ensslin MA, Koti V, Hsueh W, et al. Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J Clin Invest. 2007;117(12):3673–83.PubMedGoogle Scholar
  64. 64.
    Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q, de Frutos P Garcia, et al. TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci. 2006;33(1):96–108. doi:10.1016/j.mcn.2006.06.011 PubMedCrossRefGoogle Scholar
  65. 65.
    Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima GK. Macrophages and dendritic cells use different Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Immunol. 2007;178(9):5635–42.PubMedGoogle Scholar
  66. 66.
    Lemke G, Rothlin CV. Immunobiology of the TAM receptors. Nat Rev Immunol. 2008;8(5):327–36. doi:10.1038/nri2303.PubMedCrossRefGoogle Scholar
  67. 67.
    Bierie B, Gorska AE, Stover DG, Moses HL. TGF-beta promotes cell death and suppresses lactation during the second stage of mammary involution. J Cell Physiol. 2009;219(1):57–68. doi:10.1002/jcp.21646.PubMedCrossRefGoogle Scholar
  68. 68.
    Booth BW, Boulanger CA, Smith GH. Stem cells and the mammary microenvironment. Breast Dis. 2008;29:57–67.PubMedGoogle Scholar
  69. 69.
    Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH. An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development. 2002;129(6):1377–86.PubMedGoogle Scholar
  70. 70.
    Matulka LA, Triplett AA, Wagner KU. Parity-induced mammary epithelial cells are multipotent and express cell surface markers associated with stem cells. Dev Biol. 2007;303(1):29–44. doi:10.1016/j.ydbio.2006.12.017.PubMedCrossRefGoogle Scholar
  71. 71.
    Polyak K, Hahn WC. Roots and stems: stem cells in cancer. Nat Med. 2006;12(3):296–300. doi:10.1038/nm1379.PubMedCrossRefGoogle Scholar
  72. 72.
    Henry MD, Triplett AA, Oh KB, Smith GH, Wagner KU. Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice. Oncogene. 2004;23(41):6980–5. doi:10.1038/sj.onc.1207827.PubMedCrossRefGoogle Scholar
  73. 73.
    Franchi L, Warner N, Viani K, Nunez G. Function of Nod-like receptors in microbial recognition and host defense. Immunol Rev. 2009;227(1):106–28. doi:10.1111/j.1600-065X.2008.00734.x.PubMedCrossRefGoogle Scholar
  74. 74.
    de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6(1):24–37. doi:10.1038/nrc1782.PubMedCrossRefGoogle Scholar
  75. 75.
    Pawelek JM, Chakraborty AK. Fusion of tumour cells with bone marrow-derived cells: a unifying explanation for metastasis. Nat Rev Cancer. 2008;8(5):377–86. doi:10.1038/nrc2371.PubMedCrossRefGoogle Scholar
  76. 76.
    Baxter FO, Came PJ, Abell K, Kedjouar B, Huth M, Rajewsky K, et al. IKKbeta/2 induces TWEAK and apoptosis in mammary epithelial cells. Development. 2006;133(17):3485–94. doi:10.1242/dev.02502.PubMedCrossRefGoogle Scholar

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

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