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RANKL inhibition: a promising novel strategy for breast cancer treatment

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  • Molecular Targets in Oncology
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Abstract

The cytokine RANKL and its receptor RANK, key proteins in bone remodelling and bone metastasis, are essential for mammary gland development in mice. RANK absence or overexpression results in a lactation defect and a non-functional mammary gland. RANKL signalling mediates progesterone-induced proliferation and expansion of the stem cell compartment in the mouse mammary gland. RANK overexpressing mammary epithelial acini show hallmarks of transformation in a RANKL-dependent manner. Complementary gain- and loss-of-function approaches (RANK transgenic and knock-out mouse models and pharmacological RANKL inhibition) define a direct contribution of this pathway to progestin-driven mammary cancer. Moreover, decreased RANKL signalling attenuates preneoplasic lesions and lung metastasis in the spontaneous model of mammary tumorigenesis MMTV-neu, suggesting that RANK pathway promotes mammary tumorigenesis and metastasis in a wider tumour spectrum and beyond its established role in bone metastasis. In this review, we summarise the role of the RANKL pathway in mammary gland development, breast cancer and metastasis, and discuss the potential application of RANKL inhibition for breast cancer treatment.

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References

  1. Slamon DJ, Clark GM, Wong SG et al (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177–182

    Article  PubMed  CAS  Google Scholar 

  2. Rakha EA, Elsheikh SE, Aleskandarany MA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15:2302–2310

    Article  PubMed  CAS  Google Scholar 

  3. Lin SX, Chen J, Mazumdar M et al (2010) Molecular therapy of breast cancer: progress and future directions. Nat Rev Endocrinol 6:485–493

    Article  PubMed  CAS  Google Scholar 

  4. Wada T, Nakashima T, Hiroshi N et al (2006) RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med 12:17–25

    Article  PubMed  CAS  Google Scholar 

  5. Armstrong AP, Tometsko ME, Glaccum M et al (2002) A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J Biol Chem 277:44347–44356

    Article  PubMed  CAS  Google Scholar 

  6. Lomaga MA, Yeh WC, Sarosi I et al (1999) TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 13:1015–1024

    Article  PubMed  CAS  Google Scholar 

  7. Chang L, Karin Mammalian M (2001) MAP kinase signalling cascades. Nature 410:37–40

    Article  PubMed  CAS  Google Scholar 

  8. Wada T, Penninger JM (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene 23:2838–2849

    Article  PubMed  CAS  Google Scholar 

  9. Nakashima T, Kobayashi Y, Yamasaki S et al (2000) Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-kappaB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun 275:768–775

    Article  PubMed  CAS  Google Scholar 

  10. Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346:561–576

    Article  PubMed  CAS  Google Scholar 

  11. Dougall WC, Glaccum M, Charrier K et al (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424

    Article  PubMed  CAS  Google Scholar 

  12. Kong YY, Yoshida H, Sarosi I et al (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323

    Article  PubMed  CAS  Google Scholar 

  13. Bucay N, Sarosi I, Dunstan CR et al (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268

    Article  PubMed  CAS  Google Scholar 

  14. Mizuno A, Amizuka N, Irie K et al (1998) Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615

    Article  PubMed  CAS  Google Scholar 

  15. Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342

    Article  PubMed  CAS  Google Scholar 

  16. Leibbrandt A, Penninger JM (2008) RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 1143:123–150

    Article  PubMed  CAS  Google Scholar 

  17. Hanada R, Hanada T, Penninger JM (2010) Physiology and pathophysiology of the RANKL/RANK system. Biol Chem 391:1365–1370

    Article  PubMed  CAS  Google Scholar 

  18. Leibbrandt A, Penninger JM (2010) Novel functions of RANK(L) signaling in the immune system. Adv Exp Med Biol 658:77–94

    Article  PubMed  CAS  Google Scholar 

  19. Theill LE, Boyle WJ, Penninger JM (2002) RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol 20:795–823

    Article  PubMed  CAS  Google Scholar 

  20. Fata JE, Kong YY, Li J et al (2000) The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103:41–50

    Article  PubMed  CAS  Google Scholar 

  21. Gonzalez-Suarez E, Branstetter D, Armstrong A et al (2007) 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 27:1442–1454

    Article  PubMed  CAS  Google Scholar 

  22. Srivastava S, Matsuda M, Hou Z et al (2003) Receptor activator of NF-kappaB ligand induction via Jak2 and Stat5a in mammary epithelial cells. J Biol Chem 278:46171–46178

    Article  PubMed  CAS  Google Scholar 

  23. Mulac-Jericevic B, Lydon JP, DeMayo FJ et al (2003) Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A 100:9744–9749

    Article  PubMed  CAS  Google Scholar 

  24. Fernandez-Valdivia R, Mukherjee A, Ying Y et al (2009) The RANKL signaling axis is sufficient to elicit ductal side-branching and alveologenesis in the mammary gland of the virgin mouse. Dev Biol 328:127–139

    Article  PubMed  CAS  Google Scholar 

  25. Mukherjee A, Soyal SM, Li J et al (2010) 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 24:4408–4419

    Article  PubMed  CAS  Google Scholar 

  26. Beleut M, Rajaram RD, Caikovski M et al (2010) Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc Natl Acad Sci U S A 107:2989–2994

    Article  PubMed  CAS  Google Scholar 

  27. Cao Y, Bonizzi G, Seagroves TN et al (2001) IK-Kalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107:763–775

    Article  PubMed  CAS  Google Scholar 

  28. Shackleton M, Vaillant F, Simpson KJ et al (2006) Generation of a functional mammary gland from a single stem cell. Nature 439:84–88

    Article  PubMed  CAS  Google Scholar 

  29. Sleeman KE, Kendrick H, Ashworth A et al (2006) CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res 8:R7

    Article  PubMed  Google Scholar 

  30. Stingl J, Eirew P, Ricketson I et al (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439:993–997

    PubMed  CAS  Google Scholar 

  31. Sleeman KE, Kendrick H, Robertson D et al (2007) Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J Cell Biol 176:19–26

    Article  PubMed  CAS  Google Scholar 

  32. Asselin-Labat ML, Vaillant F, Sheridan JM et al (2010) Control of mammary stem cell function by steroid hormone signalling. Nature 465:798–802

    Article  PubMed  CAS  Google Scholar 

  33. Kendrick H, Regan JL, Magnay FA et al (2008) Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 9:591

    Article  PubMed  Google Scholar 

  34. Joshi PA, Jackson HW, Beristain AG et al (2010) Progesterone induces adult mammary stem cell expansion. Nature 465:803–807

    Article  PubMed  CAS  Google Scholar 

  35. Schramek D, Leibbrandt A, Sigl V et al (2010) Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468:98–102

    Article  PubMed  CAS  Google Scholar 

  36. Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988

    Article  PubMed  CAS  Google Scholar 

  37. Gonzalez-Suarez E, Jacob AP, Jones J et al (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468:103–107

    Article  PubMed  CAS  Google Scholar 

  38. Fernandez-Valdivia R, Mukherjee A, Creighton CJ et al (2008) Transcriptional response of the murine mammary gland to acute progesterone exposure. Endocrinology 149:6236–6250

    Article  PubMed  CAS  Google Scholar 

  39. Kelsey JL, Gammon MD, John EM (1993) Reproductive factors and breast cancer. Epidemiol Rev 15:36–47

    PubMed  CAS  Google Scholar 

  40. Hofseth LJ, Raafat AM, Osuch JR et al (1999) Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 84:4559–4565

    Article  PubMed  CAS  Google Scholar 

  41. Chlebowski RT, Hendrix SL, Langer RD et al (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 289:3243–3253

    Article  PubMed  CAS  Google Scholar 

  42. Guy CT, Webster MA, Schaller M et al (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci U S A 89:10578–10582

    Article  PubMed  CAS  Google Scholar 

  43. Tan W, Zhang W, Strasner A et al (2011) Tumourinfiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signal-ling. Nature 470:548–553

    Article  PubMed  CAS  Google Scholar 

  44. Luo JL, Tan W, Ricono JM et al (2007) Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446:690–694

    Article  PubMed  CAS  Google Scholar 

  45. Jones DH, Nakashima T, Sanchez OH et al (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696

    Article  PubMed  CAS  Google Scholar 

  46. Bhatia P, Sanders MM, Hansen MF (2005) Expression of receptor activator of nuclear factorkappaB is inversely correlated with metastatic phenotype in breast carcinoma. Clin Cancer Res 11:162–165

    PubMed  CAS  Google Scholar 

  47. Chen G, Sircar K, Aprikian A et al (2006) Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer 107:289–298

    Article  PubMed  CAS  Google Scholar 

  48. Mikami S, Katsube K, Oya M et al (2009) Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol 218:530–539

    Article  PubMed  CAS  Google Scholar 

  49. Santini D, Perrone G, Roato I et al (2011) Expression pattern of receptor activator of NFkappaB (RANK) in a series of primary solid tumors and related bone metastases. J Cell Physiol 226:780–784

    Article  PubMed  CAS  Google Scholar 

  50. Lindeman GJ, Visvader JE (2010) Insights into the cell of origin in breast cancer and breast cancer stem cells. Asia Pac J Clin Oncol 6:89–97

    Article  PubMed  Google Scholar 

  51. Visvader JE (2009) Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 23:2563–2577

    Article  PubMed  CAS  Google Scholar 

  52. Kostenuik PJ (2005) Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 5:618–625

    Article  PubMed  CAS  Google Scholar 

  53. Body JJ, Lipton A, Gralow J et al (2010) Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. J Bone Miner Res 25:440–446

    Article  PubMed  CAS  Google Scholar 

  54. Fizazi K, Lipton A, Mariette X et al (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571

    Article  PubMed  CAS  Google Scholar 

  55. Stopeck AT, Lipton A, Body JJ et al (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139

    Article  PubMed  CAS  Google Scholar 

  56. Dontu G, Wicha MS (2005) Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia. J Mammary Gland Biol Neoplasia 10:75–86

    Article  PubMed  Google Scholar 

  57. Canon J, Bryant R, Roudier M et al (2010) Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis. Bone 46:1613–1619

    Article  PubMed  CAS  Google Scholar 

  58. Holland PM, Miller R, Jones J et al (2010) Combined therapy with the RANKL inhibitor RANKFc and rhApo2L/TRAIL/dulanermin reduces bone lesions and skeletal tumor burden in a model of breast cancer skeletal metastasis. Cancer Biol Ther 9:539–550

    Article  PubMed  CAS  Google Scholar 

  59. Miller RE, Roudier M, Jones J et al (2008) RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis. Mol Cancer Ther 7:2160–2169

    Article  PubMed  CAS  Google Scholar 

  60. Virk MS, Alaee F, Petrigliano FA et al (2011) Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion. Bone 48:578–587

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Eva González-Suárez.

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González-Suárez, E. RANKL inhibition: a promising novel strategy for breast cancer treatment. Clin Transl Oncol 13, 222–228 (2011). https://doi.org/10.1007/s12094-011-0646-5

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