Skip to main content
SpringerLink
Log in

Parathyroid Hormone Related Protein (PTHrP) in Tumor Progression

  • Chapter
  • First Online:
Book cover Human Cell Transformation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 720))

Abstract

Parathyroid hormone-related protein (PTHrP) is widely expressed in fetal and adult tissues and is a key regulator for cellular calcium transport and smooth muscle cell contractility, as well as a crucial control factor in cell proliferation, development and differentiation. PTHrP stimulates or inhibits apoptosis in an autocrine/paracrine and intracrine fashion, and is particularly important for hair follicle and bone development, mammary epithelial development and tooth eruption. PTHrP’s dysregulated expression has traditionally been associated with oncogenic pathologies as the major causative agent of malignancy-associated hypercalcemia, but recent evidence revealed a driving role in skeletal metastasis progression. Here, we demonstrate that PTHrP is also closely involved in breast cancer initiation, growth and metastasis through mechanisms separate from its bone turnover action, and we suggest that PTHrP as a facilitator of oncogenes would be a novel target for therapeutic purposes.

This study was supported by grants from the Susan G. Komen Foundation (KG 100766) and the Canadian Institutes for Health Research (CIHR MOP 102555) to R. Kremer and AC Karaplis and the US Department of Defense Breast Cancer Research Program (BC023897) to AC Karaplis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Vanderschueren B et al (1994) Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia. Cancer Immunol Immunother 39:286–290

    PubMed  CAS  Google Scholar 

  2. Sugihara A et al (1998) Expression of cytokines enhancing the osteoclast activity, and parathyroid hormone-related protein in prostatic cancers before and after endocrine therapy: an immunohistochemical study. Oncol Rep 5:1389–1394

    PubMed  CAS  Google Scholar 

  3. Shibahara T, Nomura T, Cui NH, Noma H (2005) A study of osteoclast-related cytokines in mandibular invasion by squamous cell carcinoma. Int J Oral Maxillofac Surg 34:789–793

    PubMed  CAS  Google Scholar 

  4. Suzuki K, Yamada S (1994) Ascites sarcoma 180, a tumor associated with hypercalcemia, secretes potent bone-resorbing factors including transforming growth factor alpha, interleukin-1 alpha and interleukin-6. Bone Miner 27:219–233

    PubMed  CAS  Google Scholar 

  5. Martin TJ, Suva LJ (1988) Parathyroid hormone-­related protein: a novel gene product. Baillieres Clin Endocrinol Metab 2:1003–1029

    PubMed  CAS  Google Scholar 

  6. Wysolmerski JJ, Broadus AE (1994) Hypercalcemia of malignancy: the central role of parathyroid hormone-related protein. Annu Rev Med 45:189–200

    PubMed  CAS  Google Scholar 

  7. Grill V, Rankin W, Martin TJ (1998) Parathyroid hormone-related protein (PTHrP) and hypercalcaemia. Eur J Cancer 34:222–229

    PubMed  CAS  Google Scholar 

  8. Svane S (1964) Hypercalcemia in malignant disease without evidence of bone destruction. A case simulating acute hyperparathyroidism. Acta Med Scand 175:353–357

    PubMed  CAS  Google Scholar 

  9. Gellhorn A, Plimpton CH (1956) Hypercalcemia in malignant disease without evidence of bone destruction. Am J Med 21:750–759

    PubMed  CAS  Google Scholar 

  10. Omenn GS, Roth SI, Baker WH (1969) Hyperparathyroidism associated with malignant tumors of nonparathyroid origin. Cancer 24:1004–1011

    PubMed  CAS  Google Scholar 

  11. Buckle R (1974) Ectopic PTH syndrome, pseudohyperparathyroidism; hypercalcaemia of malignancy. Clin Endocrinol Metab 3:237–251

    PubMed  CAS  Google Scholar 

  12. Buckle RM, McMillan M, Mallinson C (1970) Ectopic secretion of parathyroid hormone by a renal adenocarcinoma in a patient with hypercalcaemia. Br Med J 4:724–726

    PubMed  CAS  Google Scholar 

  13. Tashjian AH Jr (1969) Animal cell cultures as a source of hormones. Biotechnol Bioeng 11:109–126

    PubMed  CAS  Google Scholar 

  14. Riggs BL, Arnaud CD, Reynolds JC, Smith LH (1971) Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer. J Clin Invest 50:2079–2083

    PubMed  CAS  Google Scholar 

  15. Benson RC Jr, Riggs BL, Pickard BM, Arnaud CD (1974) Immunoreactive forms of circulating parathyroid hormone in primary and ectopic hyperparathyroidism. J Clin Invest 54:175–181

    PubMed  Google Scholar 

  16. Moseley JM et al (1987) Parathyroid hormone-­related protein purified from a human lung cancer cell line. Proc Natl Acad Sci USA 84:5048–5052

    PubMed  CAS  Google Scholar 

  17. Strewler GJ et al (1987) Parathyroid hormonelike protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest 80:1803–1807

    PubMed  CAS  Google Scholar 

  18. Burtis WJ et al (1987) Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem 262:7151–7156

    PubMed  CAS  Google Scholar 

  19. Suva LJ et al (1987) A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 237:893–896

    PubMed  CAS  Google Scholar 

  20. Mangin M, Ikeda K, Dreyer BE, Milstone L, Broadus AE (1988) Two distinct tumor-derived, parathyroid hormone-like peptides result from alternative ribonucleic acid splicing. Mol Endocrinol 2:1049–1055

    PubMed  CAS  Google Scholar 

  21. Thiede MA, Strewler GJ, Nissenson RA, Rosenblatt M, Rodan GA (1988) Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene. Proc Natl Acad Sci USA 85:4605–4609

    PubMed  CAS  Google Scholar 

  22. Kemp BE et al (1987) Parathyroid hormone-related protein of malignancy: active synthetic fragments. Science 238:1568–1570

    PubMed  CAS  Google Scholar 

  23. Nickols GA, Nickols MA, Helwig JJ (1990) Binding of parathyroid hormone and parathyroid hormone-related protein to vascular smooth muscle of rabbit renal microvessels. Endocrinology 126:721–727

    PubMed  CAS  Google Scholar 

  24. Kao PC, Klee GG, Taylor RL, Heath H 3rd (1990) Parathyroid hormone-related peptide in plasma of patients with hypercalcemia and malignant lesions. Mayo Clin Proc 65:1399–1407

    PubMed  CAS  Google Scholar 

  25. Burtis WJ et al (1990) Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med 322:1106–1112

    PubMed  CAS  Google Scholar 

  26. Mangin M et al (1988) Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci USA 85:597–601

    PubMed  CAS  Google Scholar 

  27. Mannens M et al (1987) Regional localization of DNA probes on the short arm of chromosome 11 using aniridia-Wilms’ tumor-associated deletions. Hum Genet 75:180–187

    PubMed  CAS  Google Scholar 

  28. Yasuda T, Banville D, Hendy GN, Goltzman D (1989) Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects. J Biol Chem 264:7720–7725

    PubMed  CAS  Google Scholar 

  29. Mangin M, Ikeda K, Dreyer BE, Broadus AE (1989) Isolation and characterization of the human parathyroid hormone-like peptide gene. Proc Natl Acad Sci USA 86:2408–2412

    PubMed  CAS  Google Scholar 

  30. Mangin M, Ikeda K, Dreyer BE, Broadus AE (1990) Identification of an up-stream promoter of the human parathyroid hormone-related peptide gene. Mol Endocrinol 4:851–858

    PubMed  CAS  Google Scholar 

  31. Mangin M, Ikeda K, Broadus AE (1990) Structure of the mouse gene encoding parathyroid hormone-­related peptide. Gene 95:195–202

    PubMed  CAS  Google Scholar 

  32. Karaplis AC, Yasuda T, Hendy GN, Goltzman D, Banville D (1990) Gene-encoding parathyroid hormone-like peptide: nucleotide sequence of the rat gene and comparison with the human homologue. Mol Endocrinol 4:441–446

    PubMed  CAS  Google Scholar 

  33. Thiede MA, Rutledge SJ (1990) Nucleotide sequence of a parathyroid hormone-related peptide expressed by the 10 day chicken embryo. Nucleic Acids Res 18:3062

    PubMed  CAS  Google Scholar 

  34. Orloff JJ et al (1994) Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions. Endocr Rev 15:40–60

    PubMed  CAS  Google Scholar 

  35. Philbrick WM et al (1996) Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76:127–173

    PubMed  CAS  Google Scholar 

  36. Fenton AJ et al (1991) A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107-111]. Endocrinology 129:3424–3426

    PubMed  CAS  Google Scholar 

  37. Cornish J, Callon KE, Nicholson GC, Reid IR (1997) Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo. Endocrinology 138:1299–1304

    PubMed  CAS  Google Scholar 

  38. Blind E, Raue F, Knappe V, Schroth J, Ziegler R (1993) Cyclic AMP formation in rat bone and kidney cells is stimulated equally by parathyroid hormone-related protein (PTHrP) 1-34 and PTH 1-34. Exp Clin Endocrinol 101:150–155

    PubMed  CAS  Google Scholar 

  39. Iida-Klein A et al (1997) Mutations in the second cytoplasmic loop of the rat parathyroid hormone (PTH)/PTH-related protein receptor result in selective loss of PTH-stimulated phospholipase C activity. J Biol Chem 272:6882–6889

    PubMed  CAS  Google Scholar 

  40. Swarthout JT, D’Alonzo RC, Selvamurugan N, Partridge NC (2002) Parathyroid hormone-dependent signaling pathways regulating genes in bone cells. Gene 282:1–17

    PubMed  CAS  Google Scholar 

  41. Takasu H, Guo J, Bringhurst FR (1999) Dual signaling and ligand selectivity of the human PTH/PTHrP receptor. J Bone Miner Res 14:11–20

    PubMed  CAS  Google Scholar 

  42. Whitfield JF et al (2001) Stimulation of protein kinase C activity in cells expressing human parathyroid hormone receptors by C- and N-terminally truncated fragments of parathyroid hormone 1-34. J Bone Miner Res 16:441–447

    PubMed  CAS  Google Scholar 

  43. Yang D, Guo J, Divieti P, Bringhurst FR (2006) Parathyroid hormone activates PKC-delta and regulates osteoblastic differentiation via a PLC-independent pathway. Bone 38:485–496

    PubMed  CAS  Google Scholar 

  44. Massfelder T et al (1997) Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-­related protein in vascular smooth muscle cells: a critical role for nuclear targeting. Proc Natl Acad Sci USA 94:13630–13635

    PubMed  CAS  Google Scholar 

  45. Henderson JE et al (1995) Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol Cell Biol 15:4064–4075

    PubMed  CAS  Google Scholar 

  46. Nguyen M, He B, Karaplis A (2001) Nuclear forms of parathyroid hormone-related peptide are translated from non-AUG start sites downstream from the initiator methionine. Endocrinology 142:694–703

    PubMed  CAS  Google Scholar 

  47. Aarts MM et al (1999) Parathyroid hormone-related protein interacts with RNA. J Biol Chem 274:4832–4838

    PubMed  CAS  Google Scholar 

  48. Aarts MM et al (2001) Parathyroid hormone-related protein promotes quiescence and survival of serum-deprived chondrocytes by inhibiting rRNA synthesis. J Biol Chem 276:37934–37943

    PubMed  CAS  Google Scholar 

  49. Lam MH et al (1999) Importin beta recognizes parathyroid hormone-related protein with high affinity and mediates its nuclear import in the absence of importin alpha. J Biol Chem 274:7391–7398

    PubMed  CAS  Google Scholar 

  50. Cingolani G, Bednenko J, Gillespie MT, Gerace L (2002) Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta. Mol Cell 10:1345–1353

    PubMed  CAS  Google Scholar 

  51. Lam MH et al (2002) Nuclear transport of parathyroid hormone (PTH)-related protein is dependent on microtubules. Mol Endocrinol 16:390–401

    PubMed  CAS  Google Scholar 

  52. Jans DA, Thomas RJ, Gillespie MT (2003) Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. Vitam Horm 66:345–384

    PubMed  CAS  Google Scholar 

  53. Miao D et al (2008) Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein. Proc Natl Acad Sci USA 105:20309–20314

    PubMed  CAS  Google Scholar 

  54. Lam MH et al (1999) Phosphorylation at the cyclin-dependent kinases site (Thr85) of parathyroid ­hormone-related protein negatively regulates its nuclear localization. J Biol Chem 274:18559–18566

    PubMed  CAS  Google Scholar 

  55. Lam MH et al (1997) PTHrP and cell division: expression and localization of PTHrP in a keratinocyte cell line (HaCaT) during the cell cycle. J Cell Physiol 173:433–446

    PubMed  CAS  Google Scholar 

  56. Fenton AJ et al (1991) A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts. Endocrinology 129:1762–1768

    PubMed  CAS  Google Scholar 

  57. Fenton AJ, Martin TJ, Nicholson GC (1994) Carboxyl-terminal parathyroid hormone-related protein inhibits bone resorption by isolated chicken osteoclasts. J Bone Miner Res 9:515–519

    PubMed  CAS  Google Scholar 

  58. Kong XF et al (1994) The rat, mouse, and human genes encoding the receptor for parathyroid hormone and parathyroid hormone-related peptide are highly homologous. Biochem Biophys Res Commun 201:1058

    PubMed  CAS  Google Scholar 

  59. Datta NS, Abou-Samra AB (2009) PTH and PTHrP signaling in osteoblasts. Cell Signal 21:1245–1254

    PubMed  CAS  Google Scholar 

  60. Abou-Samra AB et al (1992) Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA 89:2732–2736

    PubMed  CAS  Google Scholar 

  61. Juppner H et al (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024–1026

    PubMed  CAS  Google Scholar 

  62. Schipani E et al (1993) Identical complementary deoxyribonucleic acids encode a human renal and bone parathyroid hormone (PTH)/PTH-related peptide receptor. Endocrinology 132:2157–2165

    PubMed  CAS  Google Scholar 

  63. Gardella TJ, Juppner H (2000) Interaction of PTH and PTHrP with their receptors. Rev Endocr Metab Disord 1:317–329

    PubMed  CAS  Google Scholar 

  64. Strewler GJ (2000) The physiology of parathyroid hormone-related protein. N Engl J Med 342:177–185

    PubMed  CAS  Google Scholar 

  65. Gensure RC, Gardella TJ, Juppner H (2005) Parathyroid hormone and parathyroid hormone-­related peptide, and their receptors. Biochem Biophys Res Commun 328:666–678

    PubMed  CAS  Google Scholar 

  66. Clemens TL et al (2001) Parathyroid hormone-­related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Br J Pharmacol 134:1113–1136

    PubMed  CAS  Google Scholar 

  67. Amling M et al (1997) Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J Cell Biol 136:205–213

    PubMed  CAS  Google Scholar 

  68. Hastings RH et al (2003) Parathyroid hormone-­related protein ameliorates death receptor-mediated apoptosis in lung cancer cells. Am J Physiol Cell Physiol 285:C1429–C1436

    PubMed  CAS  Google Scholar 

  69. Gagiannis S et al (2009) Parathyroid hormone-­related protein confers chemoresistance by blocking apoptosis signaling via death receptors and mitochondria. Int J Cancer 125:1551–1557

    PubMed  CAS  Google Scholar 

  70. Karaplis AC et al (1994) Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev 8:277–289

    PubMed  CAS  Google Scholar 

  71. Amizuka N et al (1996) Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev Biol 175:166–176

    PubMed  CAS  Google Scholar 

  72. Philbrick WM, Dreyer BE, Nakchbandi IA, Karaplis AC (1998) Parathyroid hormone-related protein is required for tooth eruption. Proc Natl Acad Sci USA 95:11846–11851

    PubMed  CAS  Google Scholar 

  73. Wysolmerski JJ et al (1998) Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development. Development 125:1285–1294

    PubMed  CAS  Google Scholar 

  74. Wysolmerski JJ, McCaughern-Carucci JF, Daifotis AG, Broadus AE, Philbrick WM (1995) Overex­pression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development. Development 121:3539–3547

    PubMed  CAS  Google Scholar 

  75. Wysolmerski JJ et al (1994) Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci USA 91:1133–1137

    PubMed  CAS  Google Scholar 

  76. Foley J et al (2001) Parathyroid hormone-related protein maintains mammary epithelial fate and triggers nipple skin differentiation during embryonic breast development. Development 128:513–525

    PubMed  CAS  Google Scholar 

  77. Ferrari SL, Rizzoli R, Bonjour JP (1992) Parathyroid hormone-related protein production by primary cultures of mammary epithelial cells. J Cell Physiol 150:304–311

    PubMed  CAS  Google Scholar 

  78. Seitz PK et al (1993) Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast. Endocrinology 133:1116–1124

    PubMed  CAS  Google Scholar 

  79. Wysolmerski JJ, Stewart AF (1998) The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor. Annu Rev Physiol 60:431–460

    PubMed  CAS  Google Scholar 

  80. Ferrari S, Rizzoli R, Chaponnier C, Gabbiani G, Bonjour JP (1993) Parathyroid hormone-related protein increases cAMP production in mammary epithelial cells. Am J Physiol 264:E471–E475

    PubMed  CAS  Google Scholar 

  81. Jemal A et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    PubMed  Google Scholar 

  82. Schilling T et al (1993) Parathyroid hormone-related protein (PTHrP) does not regulate 1,25-dihydroxyvitamin D serum levels in hypercalcemia of malignancy. J Clin Endocrinol Metab 76:801–803

    PubMed  CAS  Google Scholar 

  83. Bouizar Z, Spyratos F, Deytieux S, de Vernejoul MC, Jullienne A (1993) Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. Cancer Res 53:5076–5078

    PubMed  CAS  Google Scholar 

  84. Bucht E et al (1998) Parathyroid hormone-related protein in patients with primary breast cancer and eucalcemia. Cancer Res 58:4113–4116

    PubMed  CAS  Google Scholar 

  85. Bundred NJ et al (1991) Parathyroid hormone related protein and hypercalcaemia in breast cancer. BMJ 303:1506–1509

    PubMed  CAS  Google Scholar 

  86. Kohno N et al (1994) Parathyroid hormone-related protein in breast cancer tissues: relationship between primary and metastatic sites. Breast Cancer 1:43–49

    PubMed  Google Scholar 

  87. Bouizar Z, Spyratos F, De vernejoul MC (1999) The parathyroid hormone-related protein (PTHrP) gene: use of downstream TATA promotor and PTHrP 1-139 coding pathways in primary breast cancers vary with the occurrence of bone metastasis. J Bone Miner Res 14:406–414

    Google Scholar 

  88. Iwamura M et al (1993) Immunohistochemical localization of parathyroid hormone-related protein in human prostate cancer. Cancer Res 53:1724–1726

    PubMed  CAS  Google Scholar 

  89. Kremer R et al (1997) Ras activation of human prostate epithelial cells induces overexpression of parathyroid hormone-related peptide. Clin Cancer Res 3:855–859

    Google Scholar 

  90. Dougherty KM et al (1999) Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. Cancer Res 59:6015–6022

    PubMed  CAS  Google Scholar 

  91. Brandt DW, Burton DW, Gazdar AF, Oie HE, Deftos LJ (1991) All major lung cancer cell types produce parathyroid hormone-like protein: heterogeneity assessed by high performance liquid chromatography. Endocrinology 129:2466–2470

    PubMed  CAS  Google Scholar 

  92. Kitazawa S et al (1991) Immunohistologic evaluation of parathyroid hormone-related protein in human lung cancer and normal tissue with newly developed monoclonal antibody. Cancer 67:984–989

    PubMed  CAS  Google Scholar 

  93. Nishigaki Y, Ohsaki Y, Toyoshima E, Kikuchi K (1999) Increased serum and urinary levels of a parathyroid hormone-related protein COOH terminus in non-small cell lung cancer patients. Clin Cancer Res 5:1473–1481

    PubMed  CAS  Google Scholar 

  94. Nishihara M, Kanematsu T, Taguchi T, Razzaque MS (2007) PTHrP and tumorigenesis: is there a role in prognosis? Ann N Y Acad Sci 1117:385–392

    PubMed  CAS  Google Scholar 

  95. Nishihara M et al (1999) Clinicopathological implications of parathyroid hormone-related protein in human colorectal tumors. J Pathol 187:217–222

    PubMed  CAS  Google Scholar 

  96. Kremer R, Shustik C, Tabak T, Papavasiliou V, Goltzman D (1996) Parathyroid-hormone-related peptide in hematologic malignancies. Am J Med 100:406–411

    PubMed  CAS  Google Scholar 

  97. Alipov GK et al (1997) Expression of parathyroid hormone-related peptide (PTHrP) in gastric tumors. J Pathol 182:174–179

    PubMed  CAS  Google Scholar 

  98. Goltzman D and Kremer R (2005) Target Genes: PTHrP. In Vitamin D 2nd edition.Feldman, Pike and Glorieux editors. Elsevier Academic Press 1:737–749

    PubMed  CAS  Google Scholar 

  99. Kremer R et al (1991) Regulation of parathyroid hormone-like peptide in cultured normal human kera­tinocytes: effects of growth factors and 1,25-dihydroxyvitamin D on gene expression and secretion. J Clin Invest 87:884–893

    PubMed  Google Scholar 

  100. Esbrit P et al (2000) C-terminal parathyroid hormone-related protein increases vascular endothelial growth factor in human osteoblastic cells. J Am Soc Nephrol 11:1085–1092

    PubMed  CAS  Google Scholar 

  101. Akino K et al (2000) Parathyroid hormone-related peptide is a potent tumor angiogenic factor. Endocrinology 141:4313–4316

    PubMed  CAS  Google Scholar 

  102. Luparello C, Burtis WJ, Raue F, Birch MA, Gallagher JA (1995) Parathyroid hormone-related peptide and 8701-BC breast cancer cell growth and invasion in vitro: evidence for growth-inhibiting and invasion-promoting effects. Mol Cell Endocrinol 111:225–232

    PubMed  CAS  Google Scholar 

  103. Luparello C, Sirchia R, Pupello D (2003) PTHrP [67-86] regulates the expression of stress proteins in breast cancer cells inducing modifications in urokinase-plasminogen activator and MMP-1 expression. J Cell Sci 116:2421–2430

    PubMed  CAS  Google Scholar 

  104. Bundred NJ et al (1992) Parathyroid hormone related protein and skeletal morbidity in breast cancer. Eur J Cancer 28:690–692

    PubMed  CAS  Google Scholar 

  105. Southby J et al (1990) Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res 50:7710–7716

    PubMed  CAS  Google Scholar 

  106. Kohno N et al (1994) The expression of parathyroid hormone-related protein in human breast cancer with skeletal metastases. Surg Today 24:215–220

    PubMed  CAS  Google Scholar 

  107. Linforth R et al (2002) Coexpression of parathyroid hormone related protein and its receptor in early breast cancer predicts poor patient survival. Clin Cancer Res 8:3172–3177

    PubMed  CAS  Google Scholar 

  108. Truong NU, deB Edwardes MD, Papavasiliou V, Goltzman D, Kremer R (2003) Parathyroid hormone-related peptide and survival of patients with cancer and hypercalcemia. Am J Med 115:115–121

    Google Scholar 

  109. Martin TJ, Moseley JM (2000) Mechanisms in the skeletal complications of breast cancer. Endocr Relat Cancer 7:271–284

    PubMed  CAS  Google Scholar 

  110. Henderson MA et al (2006) Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Res 66:2250–2256

    PubMed  CAS  Google Scholar 

  111. Sato K, Onuma E, Yocum RC, Ogata E (2003) Treatment of malignancy-associated hypercalcemia and cachexia with humanized anti-parathyroid hormone-related protein antibody. Semin Oncol 30:167–173

    PubMed  CAS  Google Scholar 

  112. Saito H et al (2005) Humanized monoclonal antibody against parathyroid hormone-related protein suppresses osteolytic bone metastasis of human breast cancer cells derived from MDA-MB-231. Anticancer Res 25:3817–3823

    PubMed  CAS  Google Scholar 

  113. Falzon M, Du P (2000) Enhanced growth of MCF-7 breast cancer cells overexpressing parathyroid ­hormone-related peptide. Endocrinology 141:1882–1892

    PubMed  CAS  Google Scholar 

  114. Hauschka PV, Mavrakos AE, Iafrati MD, Doleman SE, Klagsbrun M (1986) Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J Biol Chem 261:12665–12674

    PubMed  CAS  Google Scholar 

  115. Yoneda T (2000) Cellular and molecular basis of preferential metastasis of breast cancer to bone. J Orthop Sci 5:75–81

    PubMed  CAS  Google Scholar 

  116. Lipton A (2004) Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention. J Support Oncol 2: 205–213; discussion 213–204, 216–207, 219–220

    Google Scholar 

  117. Akhtari M, Mansuri J, Newman KA, Guise TM, Seth P (2008) Biology of breast cancer bone metastasis. Cancer Biol Ther 7:3–9

    PubMed  CAS  Google Scholar 

  118. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA (2007) Molecular biology of bone metastasis. Mol Cancer Ther 6:2609–2617

    PubMed  CAS  Google Scholar 

  119. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602

    Google Scholar 

  120. Guise TA, Mundy GR (1998) Cancer and bone. Endocr Rev 19:18–54

    PubMed  CAS  Google Scholar 

  121. Mundy GR (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2:584–593

    PubMed  CAS  Google Scholar 

  122. Guise TA et al (1996) Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Invest 98:1544–1549

    PubMed  CAS  Google Scholar 

  123. Kakonen SM, Mundy GR (2003) Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer 97:834–839

    PubMed  Google Scholar 

  124. Roodman GD (2004) Mechanisms of bone metastasis. N Engl J Med 350:1655–1664

    PubMed  CAS  Google Scholar 

  125. Alokail MS (2005) Induction of erbB1 and erB2 receptors by PTHrP in breast cancer cells. AACR Meeting Abstracts 2005:1359

    Google Scholar 

  126. Chirgwin JM, Guise TA (2000) Molecular mechanisms of tumor-bone interactions in osteolytic metastases. Crit Rev Eukaryot Gene Expr 10:159–178

    PubMed  CAS  Google Scholar 

  127. Peyruchaud O (2007) Mechanisms of bone metastasis formation. J Soc Biol 201:229–236

    PubMed  CAS  Google Scholar 

  128. Wagner KU et al (2001) Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10:545–553

    PubMed  CAS  Google Scholar 

  129. Andrechek ER et al (2000) Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc Natl Acad Sci USA 97:3444–3449

    PubMed  CAS  Google Scholar 

  130. Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12:954–961

    PubMed  CAS  Google Scholar 

  131. Dilworth SM (2002) Polyoma virus middle T antigen and its role in identifying cancer-related molecules. Nat Rev Cancer 2:951–956

    PubMed  CAS  Google Scholar 

  132. Aklilu F, Park M, Goltzman D, Rabbani SA (1997) Induction of parathyroid hormone-related peptide by the Ras oncogene: role of Ras farnesylation inhibitors as potential therapeutic agents for hypercalcemia of malignancy. Cancer Res 57:4517–4522

    PubMed  CAS  Google Scholar 

  133. Shen X, Falzon M (2006) PTH-related protein upregulates integrin alpha6beta4 expression and activates Akt in breast cancer cells. Exp Cell Res 312:3822–3834

    PubMed  CAS  Google Scholar 

  134. Agouni A et al (2007) Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B. Carcinogenesis 28:1893–1901

    PubMed  CAS  Google Scholar 

  135. Fantozzi A, Christofori G (2006) Mouse models of breast cancer metastasis. Breast Cancer Res 8:212

    PubMed  Google Scholar 

  136. Husemann Y et al (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13:58–68

    PubMed  Google Scholar 

  137. Kremer R et al (2010) Parathyroid hormone-related protein (PTHrP) gene ablation in breast cancer cells inhibits invasion in vitro and metastasis in vivo: role of AKT and CXCR4. In ASBMR 2010 Annual Meeting presentation 1229 (Toronto, ON)

    Google Scholar 

  138. Ditmer J (2004) Importance of PTHrP for cancer development. J Gene Ther Mol Biol 8:451–454

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, McGill University Health Centre, 687 Pine Avenue West, Montréal, QC, Canada, H3A1A1

    Richard Kremer

  2. Department of Medicine, McGill University Health Centre, Montreal, QC, Canada

    Jiarong Li & Anne Camirand

  3. Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada

    Anne Camirand & Andrew C. Karaplis

Authors
  1. Richard Kremer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiarong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anne Camirand
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew C. Karaplis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Kremer .

Editor information

Editors and Affiliations

  1. Uniformed Services, Department of Surgery, University of the Health Sciences, South Glen Road 11455, Bethesda, 20854, Maryland, USA

    Johng S. Rhim

  2. , Department of Medicine, McGill University Health Centre, Pine Ave 687, Montreal, Québec, Canada

    Richard Kremer

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Kremer, R., Li, J., Camirand, A., Karaplis, A.C. (2011). Parathyroid Hormone Related Protein (PTHrP) in Tumor Progression. In: Rhim, J., Kremer, R. (eds) Human Cell Transformation. Advances in Experimental Medicine and Biology, vol 720. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-0254-1_12

Download citation

Publish with us

Policies and ethics

Search

Navigation