Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1996 Jul;74(2):200–207. doi: 10.1038/bjc.1996.338

A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice.

J Kurebayashi 1, M Kurosumi 1, H Sonoo 1
PMCID: PMC2074563  PMID: 8688322

Abstract

Parathyroid hormone-related protein (PTHrP) is the main cause of humoral hypercalcaemia of malignancy (HHM). We recently established a new human breast cancer cell line, designated KPL-3C, from the malignant effusion of a breast cancer patient with HHM. Morphological, cytogenetic and immunohistochemical analyses indicated that the cell line is derived from human breast cancer. The KPL-3C cells stably secrete immunoreactive PTHrP measured by a two-site immunoradiometric assay, possess both oestrogen and progesterone receptors and are tumorigenic in female nude mice. The addition of phorbol-12-myristate-13-acetate to the medium significantly increased PTHrP secretion from the cells. In contrast, hydrocortisone, medroxyprogesterone acetate and 22-oxacalcitriol decreased PTHrP secretion in a dose-dependent manner. Unexpectedly, a number of microcalcifications were observed in the transplanted tumours. Radiographical examination indicated that the microcalcifications in the tumours are very similar to those commonly observed in human breast cancer. These findings suggest that this KPL-3C cell line may be useful for studying the regulatory mechanisms of PTHrP secretion and the mechanisms that lead to the deposition of microcalcifications in breast cancer.

Full text

PDF
202

Images in this article

202Figure 1
on p.202
203Figure 2
on p.203
203Figure 3
on p.203
204Figure 4
on p.204
204Figure 5
on p.204
205Figure 7
on p.205

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bellahcène A., Merville M. P., Castronovo V. Expression of bone sialoprotein, a bone matrix protein, in human breast cancer. Cancer Res. 1994 Jun 1;54(11):2823–2826. [PubMed] [Google Scholar]
  2. Birch M. A., Carron J. A., Scott M., Fraser W. D., Gallagher J. A. Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor expression and mitogenic responses in human breast cancer cell lines. Br J Cancer. 1995 Jul;72(1):90–95. doi: 10.1038/bjc.1995.282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Body J. J., Borkowski A., Cleeren A., Bijvoet O. L. Treatment of malignancy-associated hypercalcemia with intravenous aminohydroxypropylidene diphosphonate. J Clin Oncol. 1986 Aug;4(8):1177–1183. doi: 10.1200/JCO.1986.4.8.1177. [DOI] [PubMed] [Google Scholar]
  4. Body J. J., Dumon J. C., Thirion M., Cleeren A. Circulating PTHrP concentrations in tumor-induced hypercalcemia: influence on the response to bisphosphonate and changes after therapy. J Bone Miner Res. 1993 Jun;8(6):701–706. doi: 10.1002/jbmr.5650080608. [DOI] [PubMed] [Google Scholar]
  5. Body J. J., Magritte A., Seraj F., Sculier J. P., Borkowski A. Aminohydroxypropylidene bisphosphonate (APD) treatment for tumor-associated hypercalcemia: a randomized comparison between a 3-day treatment and single 24-hour infusions. J Bone Miner Res. 1989 Dec;4(6):923–928. doi: 10.1002/jbmr.5650040617. [DOI] [PubMed] [Google Scholar]
  6. Bouizar Z., Spyratos F., Deytieux S., de Vernejoul M. C., Jullienne A. Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases. Cancer Res. 1993 Nov 1;53(21):5076–5078. [PubMed] [Google Scholar]
  7. Bundred N. J., Walker R. A., Ratcliffe W. A., Warwick J., Morrison J. M., Ratcliffe J. G. Parathyroid hormone related protein and skeletal morbidity in breast cancer. Eur J Cancer. 1992;28(2-3):690–692. doi: 10.1016/s0959-8049(05)80127-3. [DOI] [PubMed] [Google Scholar]
  8. Burtis W. J., Brady T. G., Orloff J. J., Ersbak J. B., Warrell R. P., Jr, Olson B. R., Wu T. L., Mitnick M. E., Broadus A. E., Stewart A. F. Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of cancer. N Engl J Med. 1990 Apr 19;322(16):1106–1112. doi: 10.1056/NEJM199004193221603. [DOI] [PubMed] [Google Scholar]
  9. Deftos L. J., Gazdar A. F., Ikeda K., Broadus A. E. The parathyroid hormone-related protein associated with malignancy is secreted by neuroendocrine tumors. Mol Endocrinol. 1989 Mar;3(3):503–508. doi: 10.1210/mend-3-3-503. [DOI] [PubMed] [Google Scholar]
  10. Dumon J. C., Magritte A., Body J. J. Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia. Bone Miner. 1991 Dec;15(3):257–266. doi: 10.1016/0169-6009(91)90131-i. [DOI] [PubMed] [Google Scholar]
  11. Ellison M., Woodhouse D., Hillyard C., Dowsett M., Coombes R. C., Gilby E. D., Greenberg P. B., Neville A. M. Immunoreactive calcitonin production by human lung carcinoma cells in culture. Br J Cancer. 1975 Sep;32(3):373–379. doi: 10.1038/bjc.1975.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grill V., Ho P., Body J. J., Johanson N., Lee S. C., Kukreja S. C., Moseley J. M., Martin T. J. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab. 1991 Dec;73(6):1309–1315. doi: 10.1210/jcem-73-6-1309. [DOI] [PubMed] [Google Scholar]
  13. Henderson J., Sebag M., Rhim J., Goltzman D., Kremer R. Dysregulation of parathyroid hormone-like peptide expression and secretion in a keratinocyte model of tumor progression. Cancer Res. 1991 Dec 15;51(24):6521–6528. [PubMed] [Google Scholar]
  14. Ichinose Y., Iguchi H., Ohta M., Katakami H. Establishment of lung cancer cell line producing parathyroid hormone-related protein. Cancer Lett. 1993 Oct 15;74(1-2):119–124. doi: 10.1016/0304-3835(93)90053-c. [DOI] [PubMed] [Google Scholar]
  15. Ikeda K., Ohno H., Hane M., Yokoi H., Okada M., Honma T., Yamada A., Tatsumi Y., Tanaka T., Saitoh T. Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma. J Clin Endocrinol Metab. 1994 Nov;79(5):1322–1327. doi: 10.1210/jcem.79.5.7962324. [DOI] [PubMed] [Google Scholar]
  16. Inoue D., Matsumoto T., Ogata E., Ikeda K. 22-Oxacalcitriol, a noncalcemic analogue of calcitriol, suppresses both cell proliferation and parathyroid hormone-related peptide gene expression in human T cell lymphotrophic virus, type I-infected T cells. J Biol Chem. 1993 Aug 5;268(22):16730–16736. [PubMed] [Google Scholar]
  17. Kanbara Y., Kono N., Nakaya M., Ishikawa Y., Fujiwara O., Kitazawa R., Kitazawa S. [Immunohistological evaluation of parathyroid hormone-related protein in breast cancer with and without calcification on mammography]. Nihon Geka Gakkai Zasshi. 1993 Apr;94(4):394–399. [PubMed] [Google Scholar]
  18. Kitazawa S., Fukase M., Kitazawa R., Takenaka A., Gotoh A., Fujita T., Maeda S. Immunohistologic evaluation of parathyroid hormone-related protein in human lung cancer and normal tissue with newly developed monoclonal antibody. Cancer. 1991 Feb 15;67(4):984–989. doi: 10.1002/1097-0142(19910215)67:4<984::aid-cncr2820670421>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  19. Kohno N., Kitazawa S., Fukase M., Sakoda Y., Kanbara Y., Furuya Y., Ohashi O., Ishikawa Y., Saitoh Y. The expression of parathyroid hormone-related protein in human breast cancer with skeletal metastases. Surg Today. 1994;24(3):215–220. doi: 10.1007/BF02032890. [DOI] [PubMed] [Google Scholar]
  20. Kohno N, Kitazawa S, Sakoda Y, Kanbara Y, Furuya Y, Ohashi O, Kitazawa R. Parathyroid Hormone-related Protein in Breast Cancer Tissues: Relationship between Primary and Metastatic Sites. Breast Cancer. 1994 Jul 30;1(1):43–49. doi: 10.1007/BF02967374. [DOI] [PubMed] [Google Scholar]
  21. Kremer R., Karaplis A. C., Henderson J., Gulliver W., Banville D., Hendy G. N., Goltzman D. Regulation of parathyroid hormone-like peptide in cultured normal human keratinocytes. Effect of growth factors and 1,25 dihydroxyvitamin D3 on gene expression and secretion. J Clin Invest. 1991 Mar;87(3):884–893. doi: 10.1172/JCI115094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kurebayashi J., Kurosumi M., Sonoo H. A new human breast cancer cell line, KPL-1 secretes tumour-associated antigens and grows rapidly in female athymic nude mice. Br J Cancer. 1995 Apr;71(4):845–853. doi: 10.1038/bjc.1995.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kurebayashi J., McLeskey S. W., Johnson M. D., Lippman M. E., Dickson R. B., Kern F. G. Quantitative demonstration of spontaneous metastasis by MCF-7 human breast cancer cells cotransfected with fibroblast growth factor 4 and LacZ. Cancer Res. 1993 May 1;53(9):2178–2187. [PubMed] [Google Scholar]
  24. Mangin M., Webb A. C., Dreyer B. E., Posillico J. T., Ikeda K., Weir E. C., Stewart A. F., Bander N. H., Milstone L., Barton D. E. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sci U S A. 1988 Jan;85(2):597–601. doi: 10.1073/pnas.85.2.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Martin T. J. Humoral hypercalcemia of malignancy. Bone Miner. 1988 Apr;4(1):83–89. [PubMed] [Google Scholar]
  26. Merryman J. I., Rosol T. J., Brooks C. L., Capen C. C. Separation of parathyroid hormone-like activity from transforming growth factor-alpha and -beta in the canine adenocarcinoma (CAC-8) model of humoral hypercalcemia of malignancy. Endocrinology. 1989 May;124(5):2456–2463. doi: 10.1210/endo-124-5-2456. [DOI] [PubMed] [Google Scholar]
  27. Miyake Y., Yamaguchi K., Honda S., Nagasaki K., Tsuchihashi T., Mori M., Kimura S., Abe K. Production of parathyroid hormone-related protein in tumour xenografts in nude mice presenting with hypercalcaemia. Br J Cancer. 1991 Feb;63(2):252–256. doi: 10.1038/bjc.1991.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Moll R., Franke W. W., Schiller D. L., Geiger B., Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982 Nov;31(1):11–24. doi: 10.1016/0092-8674(82)90400-7. [DOI] [PubMed] [Google Scholar]
  29. Mundy G. R. Pathophysiology of cancer-associated hypercalcemia. Semin Oncol. 1990 Apr;17(2 Suppl 5):10–15. [PubMed] [Google Scholar]
  30. Powell G. J., Southby J., Danks J. A., Stillwell R. G., Hayman J. A., Henderson M. A., Bennett R. C., Martin T. J. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res. 1991 Jun 1;51(11):3059–3061. [PubMed] [Google Scholar]
  31. Ratcliffe W. A., Hutchesson A. C., Bundred N. J., Ratcliffe J. G. Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia. Lancet. 1992 Jan 18;339(8786):164–167. doi: 10.1016/0140-6736(92)90220-w. [DOI] [PubMed] [Google Scholar]
  32. Sato K., Fujii Y., Ono M., Nomura H., Shizume K. Production of interleukin 1 alpha-like factor and colony-stimulating factor by a squamous cell carcinoma of the thyroid (T3M-5) derived from a patient with hypercalcemia and leukocytosis. Cancer Res. 1987 Dec 15;47(24 Pt 1):6474–6480. [PubMed] [Google Scholar]
  33. Sebag M., Henderson J., Goltzman D., Kremer R. Regulation of parathyroid hormone-related peptide production in normal human mammary epithelial cells in vitro. Am J Physiol. 1994 Sep;267(3 Pt 1):C723–C730. doi: 10.1152/ajpcell.1994.267.3.C723. [DOI] [PubMed] [Google Scholar]
  34. Sickles E. A. Breast calcifications: mammographic evaluation. Radiology. 1986 Aug;160(2):289–293. doi: 10.1148/radiology.160.2.3726103. [DOI] [PubMed] [Google Scholar]
  35. Skinner M. A., Swain M., Simmons R., McCarty K. S., Jr, Sullivan D. C., Iglehart J. D. Nonpalpable breast lesions at biopsy. A detailed analysis of radiographic features. Ann Surg. 1988 Aug;208(2):203–208. doi: 10.1097/00000658-198808000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Snyder R. E., Rosen P. Radiography of breast specimens. Cancer. 1971 Dec;28(6):1608–1611. doi: 10.1002/1097-0142(197112)28:6<1608::aid-cncr2820280640>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  37. Soule H. D., Vazguez J., Long A., Albert S., Brennan M. A human cell line from a pleural effusion derived from a breast carcinoma. J Natl Cancer Inst. 1973 Nov;51(5):1409–1416. doi: 10.1093/jnci/51.5.1409. [DOI] [PubMed] [Google Scholar]
  38. Southby J., Kissin M. W., Danks J. A., Hayman J. A., Moseley J. M., Henderson M. A., Bennett R. C., Martin T. J. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res. 1990 Dec 1;50(23):7710–7716. [PubMed] [Google Scholar]
  39. Strewler G. J., Williams R. D., Nissenson R. A. Human renal carcinoma cells produce hypercalcemia in the nude mouse and a novel protein recognized by parathyroid hormone receptors. J Clin Invest. 1983 Mar;71(3):769–774. doi: 10.1172/JCI110825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Suva L. J., Winslow G. A., Wettenhall R. E., Hammonds R. G., Moseley J. M., Diefenbach-Jagger H., Rodda C. P., Kemp B. E., Rodriguez H., Chen E. Y. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987 Aug 21;237(4817):893–896. doi: 10.1126/science.3616618. [DOI] [PubMed] [Google Scholar]
  41. Tabuenca A., Mohan S., Garberoglio C. A., Borgen P. I., Rosol T., Linkhart T. A. Parathyroid hormone-related protein: primary osteolytic factor produced by breast tumor cells in vitro? World J Surg. 1995 Mar-Apr;19(2):292–298. doi: 10.1007/BF00308642. [DOI] [PubMed] [Google Scholar]
  42. Vargas S. J., Gillespie M. T., Powell G. J., Southby J., Danks J. A., Moseley J. M., Martin T. J. Localization of parathyroid hormone-related protein mRNA expression in breast cancer and metastatic lesions by in situ hybridization. J Bone Miner Res. 1992 Aug;7(8):971–979. doi: 10.1002/jbmr.5650070814. [DOI] [PubMed] [Google Scholar]
  43. Walls J., Ratcliffe W. A., Howell A., Bundred N. J. Response to intravenous bisphosphonate therapy in hypercalcaemic patients with and without bone metastases: the role of parathyroid hormone-related protein. Br J Cancer. 1994 Jul;70(1):169–172. doi: 10.1038/bjc.1994.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. de Lafontan B., Daures J. P., Salicru B., Eynius F., Mihura J., Rouanet P., Lamarque J. L., Naja A., Pujol H. Isolated clustered microcalcifications: diagnostic value of mammography--series of 400 cases with surgical verification. Radiology. 1994 Feb;190(2):479–483. doi: 10.1148/radiology.190.2.8284403. [DOI] [PubMed] [Google Scholar]
  45. de Miguel F., Esbrit P. Isolation of a 18,000-Da molecular weight form of parathyroid hormone-related protein from the rat Walker carcinosarcoma 256. Cancer Lett. 1992 Oct 21;66(3):201–206. doi: 10.1016/0304-3835(92)90248-t. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES