RANKL/RANK - From bone physiology to breast cancer

Cytokine and Growth Factor Reviews

Volumn 25, Issue 2, 2014, Pages 205-214

  Sigl, Verena ^a   Penninger, Josef M ^a  

^a ERICH SCHMID INSTITUTE OF MATERIALS SCIENCE   (Austria)

Author keywords

Bone; Breast cancer; Mammary gland; RANK; RANKL

Indexed keywords

OSTEOCLAST DIFFERENTIATION FACTOR; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; OSTEOPROTEGERIN; TNFRSF11A PROTEIN, HUMAN; TNFRSF11B PROTEIN, HUMAN; TNFSF11 PROTEIN, HUMAN;

BONE DEVELOPMENT; BONE METABOLISM; BONE METASTASIS; BONE TURNOVER; BREAST CANCER; BREAST CARCINOGENESIS; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; MAMMARY GLAND; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; STEM CELL; ANIMAL; AUTOIMMUNE DISEASE; BONE; BONE DISEASE; BONE TUMOR; BREAST TUMOR; CELL TRANSFORMATION; FEMALE; GENETICS; METABOLISM; MOUSE; OSTEOPOROSIS; PATHOLOGY; PHYSIOLOGY;

ANIMALS; AUTOIMMUNE DISEASES; BONE AND BONES; BONE DISEASES; BONE NEOPLASMS; BREAST NEOPLASMS; CELL TRANSFORMATION, NEOPLASTIC; FEMALE; HUMANS; MICE; NF-KAPPA B; OSTEOPOROSIS; OSTEOPROTEGERIN; RANK LIGAND; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B;

EID: 84899072812     PISSN: 13596101     EISSN: 18790305     Source Type: Journal    
DOI: 10.1016/j.cytogfr.2014.01.002     Document Type: Review

References (122)

1. Anderson D.M., Maraskovsky E., Billingsley W.L., Dougall W.C., Tometsko M.E., Roux E.R., et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997, 390(6656):175-179.
2. Lacey D.L., Timms E., Tan H.L., Kelley M.J., Dunstan C.R., Burgess T., et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 93(2):165-176.
3. Wong B.R., Josien R., Lee S.Y., Sauter B., Li H.L., Steinman R.M., et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J Exp Med 1997, 186(12):2075-2080.
4. Yasuda H., Shima N., Nakagawa N., Yamaguchi K., Kinosaki M., Mochizuki S., et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998, 95(7):3597-3602.
5. Nakagawa N., Kinosaki M., Yamaguchi K., Shima N., Yasuda H., Yano K., et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun 1998, 253(2):395-400.
6. Simonet W.S., Lacey D.L., Dunstan C.R., Kelley M., Chang M.S., Luthy R., et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997, 89(2):309-319.
7. Tsuda E., Goto M., Mochizuki S., Yano K., Kobayashi F., Morinaga T., et al. Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 1997, 234(1):137-142.
8. Kong Y.Y., Yoshida H., Sarosi I., Tan H.L., Timms E., Capparelli C., et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999, 397(6717):315-323.
9. Leibbrandt A., Penninger J.M. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 2008, 1143:123-150.
10. Seeman E., Delmas P.D. Bone quality - the material and structural basis of bone strength and fragility. N Engl J Med 2006, 354(21):2250-2261.
11. Wada T., Nakashima T., Hiroshi N., Penninger J.M. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 2006, 12(1):17-25.
12. Rachner T.D., Khosla S., Hofbauer L.C. Osteoporosis: now and the future. Lancet 2011, 377(9773):1276-1287.
13. Dougall W.C., Glaccum M., Charrier K., Rohrbach K., Brasel K., De Smedt T., et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999, 13(18):2412-2424.
14. Bucay N., Sarosi I., Dunstan C.R., Morony S., Tarpley J., Capparelli C., et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998, 12(9):1260-1268.
15. Mizuno A., Amizuka N., Irie K., Murakami A., Fujise N., Kanno T., et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 1998, 247(3):610-615.
16. Lomaga M.A., Yeh W.C., Sarosi I., Duncan G.S., Furlonger C., Ho A., et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 1999, 13(8):1015-1024.
17. Wong B.R., Besser D., Kim N., Arron J.R., Vologodskaia M., Hanafusa H., et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 1999, 4(6):1041-1049.
18. Wada T., Nakashima T., Oliveira-dos-Santos A.J., Gasser J., Hara H., Schett G., et al. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med 2005, 11(4):394-399.
19. Takayanagi H., Kim S., Koga T., Nishina H., Isshiki M., Yoshida H., et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 2002, 3(6):889-901.
20. Hofbauer L.C., Khosla S., Dunstan C.R., Lacey D.L., Spelsberg T.C., Riggs B.L. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999, 140(9):4367-4370.
21. Cummings S.R., San Martin J., McClung M.R., Siris E.S., Eastell R., Reid I.R., et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009, 361(8):756-765.
22. Smith M.R., Egerdie B., Hernandez Toriz N., Feldman R., Tammela T.L., Saad F., et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009, 361(8):745-755.
23. Bone H.G., Bolognese M.A., Yuen C.K., Kendler D.L., Wang H., Liu Y., et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008, 93(6):2149-2157.
24. McClung M.R., Lewiecki E.M., Cohen S.B., Bolognese M.A., Woodson G.C., Moffett A.H., et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006, 354(8):821-831.
25. Leibbrandt A., Penninger J.M. TNF conference 2009: beyond bones - RANKL/RANK in the immune system. Adv Exp Med Biol 2011, 691:5-22.
26. Hughes A.E., Ralston S.H., Marken J., Bell C., MacPherson H., Wallace R.G., et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 2000, 24(1):45-48.
27. Whyte M.P., Hughes A.E. Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. J Bone Miner Res 2002, 17(1):26-29.
28. Whyte M.P., Obrecht S.E., Finnegan P.M., Jones J.L., Podgornik M.N., McAlister W.H., et al. Osteoprotegerin deficiency and juvenile Paget's disease. N Engl J Med 2002, 347(3):175-184.
29. Pangrazio A., Cassani B., Guerrini M.M., Crockett J.C., Marrella V., Zammataro L., et al. RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations. J Bone Miner Res 2012, 27(2):342-351.
30. Gough A.K., Lilley J., Eyre S., Holder R.L., Emery P. Generalised bone loss in patients with early rheumatoid arthritis. Lancet 1994, 344(8914):23-27.
31. Cochran D.L. Inflammation and bone loss in periodontal disease. J Periodontol 2008, 79(Suppl. 8):1569-1576.
32. Kong Y.Y., Feige U., Sarosi I., Bolon B., Tafuri A., Morony S., et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1999, 402(6759):304-309.
33. Waterhouse P., Penninger J.M., Timms E., Wakeham A., Shahinian A., Lee K.P., et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995, 270(5238):985-988.
34. Feldmann M., Brennan F.M., Maini R.N. Rheumatoid arthritis. Cell 1996, 85(3):307-310.
35. Bendele A., McComb J., Gould T., McAbee T., Sennello G., Chlipala E., et al. Animal models of arthritis: relevance to human disease. Toxicol Pathol 1999, 27(1):134-142.
36. Redlich K., Hayer S., Maier A., Dunstan C.R., Tohidast-Akrad M., Lang S., et al. Tumor necrosis factor alpha-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin. Arthritis Rheum 2002, 46(3):785-792.
37. Romas E., Sims N.A., Hards D.K., Lindsay M., Quinn J.W., Ryan P.F., et al. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 2002, 161(4):1419-1427.
38. Cohen S.B., Dore R.K., Lane N.E., Ory P.A., Peterfy C.G., Sharp J.T., et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum 2008, 58(5):1299-1309.
39. Ebeling P.R., Erbas B., Hopper J.L., Wark J.D., Rubinfeld A.R. Bone mineral density and bone turnover in asthmatics treated with long-term inhaled or oral glucocorticoids. J Bone Miner Res 1998, 13(8):1283-1289.
40. Oliveri M.B., Mautalen C.A., Rodriguez Fuchs C.A., Romanelli M.C. Vertebral compression fractures at the onset of acute lymphoblastic leukemia in a child. Henry Ford Hosp Med J 1991, 39(1):45-48.
41. Piepkorn B., Kann P., Forst T., Andreas J., Pfutzner A., Beyer J. Bone mineral density and bone metabolism in diabetes mellitus. Horm Metab Res 1997, 29(11):584-591.
42. Stellon A.J., Davies A., Compston J., Williams R. Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy. Gastroenterology 1985, 89(5):1078-1083.
43. Brandt J., Haibel H., Cornely D., Golder W., Gonzalez J., Reddig J., et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum 2000, 43(6):1346-1352.
44. Takayanagi H., Ogasawara K., Hida S., Chiba T., Murata S., Sato K., et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature 2000, 408(6812):600-605.
45. Horwood N.J., Elliott J., Martin T.J., Gillespie M.T. IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro. J Immunol 2001, 166(8):4915-4921.
46. Abu-Amer Y. IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB. J Clin Invest 2001, 107(11):1375-1385.
47. Bendixen A.C., Shevde N.K., Dienger K.M., Willson T.M., Funk C.D., Pike J.W. IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1. Proc Natl Acad Sci U S A 2001, 98(5):2443-2448.
48. Bettelli E., Korn T., Oukka M., Kuchroo V.K. Induction and effector functions of T(H)17 cells. Nature 2008, 453(7198):1051-1057.
49. Sato K., Suematsu A., Okamoto K., Yamaguchi A., Morishita Y., Kadono Y., et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006, 203(12):2673-2682.
50. Kotake S., Udagawa N., Takahashi N., Matsuzaki K., Itoh K., Ishiyama S., et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999, 103(9):1345-1352.
51. Komatsu N., Okamoto K., Sawa S., Nakashima T., Oh-Hora M., Kodama T., et al. Pathogenic conversion of Foxp3 T cells into T17 cells in autoimmune arthritis. Nat Med 2014, 20:62-68.
52. Alimzhanov M.B., Kuprash D.V., Kosco-Vilbois M.H., Luz A., Turetskaya R.L., Tarakhovsky A., et al. Abnormal development of secondary lymphoid tissues in lymphotoxin beta-deficient mice. Proc Natl Acad Sci U S A 1997, 94(17):9302-9307.
53. Futterer A., Mink K., Luz A., Kosco-Vilbois M.H., Pfeffer K. The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 1998, 9(1):59-70.
54. Koni P.A., Sacca R., Lawton P., Browning J.L., Ruddle N.H., Flavell R.A. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 1997, 6(4):491-500.
55. Matsumoto M., Mariathasan S., Nahm M.H., Baranyay F., Peschon J.J., Chaplin D.D. Role of lymphotoxin and the type I TNF receptor in the formation of germinal centers. Science 1996, 271(5253):1289-1291.
56. Yokota Y., Mansouri A., Mori S., Sugawara S., Adachi S., Nishikawa S., et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 1999, 397(6721):702-706.
57. Sobacchi C., Frattini A., Guerrini M.M., Abinun M., Pangrazio A., Susani L., et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 2007, 39(8):960-962.
58. Kim D., Mebius R.E., MacMicking J.D., Jung S., Cupedo T., Castellanos Y., et al. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med 2000, 192(10):1467-1478.
59. Chen Y., Wang X., Di L., Fu G., Bai L., Liu J., et al. Phospholipase Cgamma2 mediates RANKL-stimulated lymph node organogenesis and osteoclastogenesis. J Biol Chem 2008, 283(43):29593-29601.
60. Banchereau J., Steinman R.M. Dendritic cells and the control of immunity. Nature 1998, 392(6673):245-252.
61. Ingulli E., Mondino A., Khoruts A., Jenkins M.K. In vivo detection of dendritic cell antigen presentation to CD4(+) T cells. J Exp Med 1997, 185(12):2133-2141.
62. Wang J., Zheng L., Lobito A., Chan F.K., Dale J., Sneller M., et al. Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 1999, 98(1):47-58.
63. Josien R., Wong B.R., Li H.L., Steinman R.M., Choi Y. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol 1999, 162(5):2562-2568.
64. Josien R., Li H.L., Ingulli E., Sarma S., Wong B.R., Vologodskaia M., et al. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J Exp Med 2000, 191(3):495-502.
65. Guerrini M.M., Sobacchi C., Cassani B., Abinun M., Kilic S.S., Pangrazio A., et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 2008, 83(1):64-76.
66. Perlot T., Penninger J.M. Development and function of murine B cells lacking RANK. J Immunol 2012, 188(3):1201-1205.
67. Knoop K.A., Kumar N., Butler B.R., Sakthivel S.K., Taylor R.T., Nochi T., et al. RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. J Immunol 2009, 183(9):5738-5747.
68. Akiyama T., Shimo Y., Yanai H., Qin J., Ohshima D., Maruyama Y., et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 2008, 29(3):423-437.
69. Hikosaka Y., Nitta T., Ohigashi I., Yano K., Ishimaru N., Hayashi Y., et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 2008, 29(3):438-450.
70. Rossi S.W., Kim M.Y., Leibbrandt A., Parnell S.M., Jenkinson W.E., Glanville S.H., et al. RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J Exp Med 2007, 204(6):1267-1272.
71. Starr T.K., Jameson S.C., Hogquist K.A. Positive and negative selection of T cells. Annu Rev Immunol 2003, 21:139-176.
72. Anderson M.S., Venanzi E.S., Klein L., Chen Z., Berzins S.P., Turley S.J., et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science 2002, 298(5597):1395-1401.
73. Loser K., Mehling A., Loeser S., Apelt J., Kuhn A., Grabbe S., et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat Med 2006, 12(12):1372-1379.
74. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005, 6(4):345-352.
75. Totsuka T., Kanai T., Nemoto Y., Tomita T., Okamoto R., Tsuchiya K., et al. RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis. J Immunol 2009, 182(10):6079-6087.
76. Christofori G. New signals from the invasive front. Nature 2006, 441(7092):444-450.
77. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 1989, 8(2):98-101.
78. Jones D.H., Nakashima T., Sanchez O.H., Kozieradzki I., Komarova S.V., Sarosi I., et al. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 2006, 440(7084):692-696.
79. Canon J.R., Roudier M., Bryant R., Morony S., Stolina M., Kostenuik P.J., et al. Inhibition of RANKL blocks skeletal tumor progression and improves survival in a mouse model of breast cancer bone metastasis. Clin Exp Metastasis 2008, 25(2):119-129.
80. Morony S., Capparelli C., Sarosi I., Lacey D.L., Dunstan C.R., Kostenuik P.J. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res 2001, 61(11):4432-4436.
81. Blake M.L., Tometsko M., Miller R., Jones J.C., Dougall W.C. RANK expression on breast cancer cells promotes skeletal metastasis. Clin Exp Metastasis 2013.
82. Palafox M., Ferrer I., Pellegrini P., Vila S., Hernandez-Ortega S., Urruticoechea A., et al. RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res 2012, 72(11):2879-2888.
83. Tan W., Zhang W., Strasner A., Grivennikov S., Cheng J.Q., Hoffman R.M., et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 2011, 470(7335):548-553.
84. Fata J.E., Kong Y.Y., Li J., Sasaki T., Irie-Sasaki J., Moorehead R.A., et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000, 103(1):41-50.
85. Hennighausen L., Robinson G.W. Signaling pathways in mammary gland development. Dev Cell 2001, 1(4):467-475.
86. Silberstein G.B., Van Horn K., Hrabeta-Robinson E., Compton J. Estrogen-triggered delays in mammary gland gene expression during the estrous cycle: evidence for a novel timing system. J Endocrinol 2006, 190(2):225-239.
87. Asselin-Labat M.L., Vaillant F., Sheridan J.M., Pal B., Wu D., Simpson E.R., et al. Control of mammary stem cell function by steroid hormone signalling. Nature 2010, 465(7299):798-802.
88. Joshi P.A., Jackson H.W., Beristain A.G., Di Grappa M.A., Mote P.A., Clarke C.L., et al. Progesterone induces adult mammary stem cell expansion. Nature 2010, 465(7299):803-807.
89. Gonzalez-Suarez E., Branstetter D., Armstrong A., Dinh H., Blumberg H., Dougall W.C. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol Cell Biol 2007, 27(4):1442-1454.
90. Fernandez-Valdivia R., Mukherjee A., Ying Y., Li J., Paquet M., DeMayo F.J., et al. The RANKL signaling axis is sufficient to elicit ductal side-branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol 2009, 328(1):127-139.
91. Schramek D., Leibbrandt A., Sigl V., Kenner L., Pospisilik J.A., Lee H.J., et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 2010, 468(7320):98-102.
92. Mulac-Jericevic B., Lydon J.P., DeMayo F.J., Conneely O.M. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A 2003, 100(17):9744-9749.
93. Mukherjee A., Soyal S.M., Li J., Ying Y., He B., DeMayo F.J., et al. Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J 2010, 24(11):4408-4419.
94. Lee H.J., Gallego-Ortega D., Ledger A., Schramek D., Joshi P., Szwarc M.M., et al. Progesterone drives mammary secretory differentiation via RankL-mediated induction of Elf5 in luminal progenitor cells. Development 2013, 140(7):1397-1401.
95. Brisken C., Kaur S., Chavarria T.E., Binart N., Sutherland R.L., Weinberg R.A., et al. Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 1999, 210(1):96-106.
96. Liu X., Robinson G.W., Wagner K.U., Garrett L., Wynshaw-Boris A., Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 1997, 11(2):179-186.
97. Srivastava S., Matsuda M., Hou Z., Bailey J.P., Kitazawa R., Herbst M.P., et al. Receptor activator of NF-kappaB ligand induction via Jak2 and Stat5a in mammary epithelial cells. J Biol Chem 2003, 278(46):46171-46178.
98. Cao Y., Bonizzi G., Seagroves T.N., Greten F.R., Johnson R., Schmidt E.V., et al. IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 2001, 107(6):763-775.
99. Fantl V., Edwards P.A., Steel J.H., Vonderhaar B.K., Dickson C. Impaired mammary gland development in Cyl-1(-/-) mice during pregnancy and lactation is epithelial cell autonomous. Dev Biol 1999, 212(1):1-11.
100. Fantl V., Stamp G., Andrews A., Rosewell I., Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev 1995, 9(19):2364-2372.
101. Mori S., Nishikawa S.I., Yokota Y. Lactation defect in mice lacking the helix-loop-helix inhibitor Id2. EMBO J 2000, 19(21):5772-5781.
102. Beleut M., Rajaram R.D., Caikovski M., Ayyanan A., Germano D., Choi Y., et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci U S A 2010, 107(7):2989-2994.
103. Cao Y., Luo J.L., Karin M. IkappaB kinase alpha kinase activity is required for self-renewal of ErbB2/Her2-transformed mammary tumor-initiating cells. Proc Natl Acad Sci U S A 2007, 104(40):15852-15857.
104. Kim N.S., Kim H.J., Koo B.K., Kwon M.C., Kim Y.W., Cho Y., et al. Receptor activator of NF-kappaB ligand regulates the proliferation of mammary epithelial cells via Id2. Mol Cell Biol 2006, 26(3):1002-1013.
105. Shackleton M., Vaillant F., Simpson K.J., Stingl J., Smyth G.K., Asselin-Labat M.L., et al. Generation of a functional mammary gland from a single stem cell. Nature 2006, 439(7072):84-88.
106. Stingl J., Eirew P., Ricketson I., Shackleton M., Vaillant F., Choi D., et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006, 439(7079):993-997.
107. Van Keymeulen A., Rocha A.S., Ousset M., Beck B., Bouvencourt G., Rock J., et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 2011, 479(7372):189-193.
108. Kelsey J.L., Gammon M.D., John E.M. Reproductive factors and breast cancer. Epidemiol Rev 1993, 15(1):36-47.
109. Theill L.E., Boyle W.J., Penninger J.M. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 2002, 20:795-823.
110. Desantis C., Ma J., Bryan L., Jemal A. Breast cancer statistics. CA Cancer J Clin 2013.
111. Jasienska G., Thune I. Lifestyle, hormones, and risk of breast cancer. Br Med J 2001, 322(7286):586-587.
112. Conneely O.M., Jericevic B.M., Lydon J.P. Progesterone receptors in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia 2003, 8(2):205-214.
113. Oakes S.R., Robertson F.G., Kench J.G., Gardiner-Garden M., Wand M.P., Green J.E., et al. Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions. Oncogene 2007, 26(4):543-553.
114. Tworoger S.S., Eliassen A.H., Rosner B., Sluss P., Hankinson S.E. Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Res 2004, 64(18):6814-6819.
115. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003, 362(9382):419-427.
116. Rossouw J.E., Anderson G.L., Prentice R.L., LaCroix A.Z., Kooperberg C., Stefanick M.L., et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002, 288(3):321-333.
117. Manson J.E., Chlebowski R.T., Stefanick M.L., Aragaki A.K., Rossouw J.E., Prentice R.L., et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. J Am Med Assoc 2013, 310(13):1353-1368.
118. Gonzalez-Suarez E., Jacob A.P., Jones J., Miller R., Roudier-Meyer M.P., Erwert R., et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010, 468(7320):103-107.
119. Hanada R., Leibbrandt A., Hanada T., Kitaoka S., Furuyashiki T., Fujihara H., et al. Central control of fever and female body temperature by RANKL/RANK. Nature 2009, 462(7272):505-509.
120. Duheron V., Hess E., Duval M., Decossas M., Castaneda B., Klopper J.E., et al. Receptor activator of NF-kappaB (RANK) stimulates the proliferation of epithelial cells of the epidermo-pilosebaceous unit. Proc Natl Acad Sci U S A 2011, 108(13):5342-5347.
121. Kiechl S., Wittmann J., Giaccari A., Knoflach M., Willeit P., Bozec A., et al. Blockade of receptor activator of nuclear factor-kappaB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med 2013, 19(3):358-363.
122. Bellamy L., Casas J.P., Hingorani A.D., Williams D. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 2009, 373(9677):1773-1779.