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BMC Cancer

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Open Access 01-12-2015 | Research article

Co-expression of parathyroid hormone related protein and TGF-beta in breast cancer predicts poor survival outcome

Authors: Cheng Xu, Zhengyuan Wang, Rongrong Cui, Hongyu He, Xiaoyan Lin, Yuan Sheng, Hongwei Zhang

Published in: BMC Cancer | Issue 1/2015

Abstract

Background

Better methods to predict prognosis can play a supplementary role in administering individualized treatment for breast cancer patients. Altered expressions of PTHrP and TGF-β have been observed in various types of human cancers. The objective of the current study was to evaluate the association of PTHrP and TGF-β level with the clinicopathological features of the breast cancer patients.

Methods

Immunohistochemistry was used to examine PTHrP and TGF-β protein expression in 497 cases of early breast cancer, and Kaplan-Meier method and COX’s Proportional Hazard Model were applied to the prognostic value of PTHrP and TGF-β expression.

Results

Both over-expressed TGF-β and PTHrP were correlated with the tumor in larger size, higher proportion of axillary lymph node metastasis and later clinical stage. Additionally, the tumors with a high TGF-β level developed poor differentiation, and only TGF-β expression was associated with disease-free survival (DFS) of the breast cancer patients. Followed up for a median of 48 months, it was found that only the patients with negative TGF-β expression had longer DFS (P < 0.05, log-rank test). Nevertheless, those with higher PTHrP expression tended to show a higher rate of bone metastasis (67.6 % vs. 45.8 %, P = 0.019). In ER negative subgroup, those who developed PTHrP positive expression presented poor prognosis (P < 0.05, log-rank test). The patients with both positive TGF-β and PTHrP expression were significantly associated with the high risk of metastases. As indicated by Cox’s regression analysis, TGF-β expression and the high proportion of axillary lymph node metastasis served as significant independent predictors for breast cancer recurrence.

Conclusions

TGF-β and PTHrP were confirmed to be involved in regulating the malignant progression in breast cancer, and PTHrP expression, to be associated with bone metastasis as a potential prognostic marker in ER negative breast cancer.

Benson JR, Jatoi I, Keisch M, Esteva FJ, Makris A, Jordan VC. Early breast cancer. Lancet. 2009;373(9673):1463–79. doi:10.1016/S0140-6736(09)60316-0.CrossRefPubMed

Weigelt B, Peterse JL, van ’t Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5(8):591–602. doi:10.1038/nrc1670.CrossRefPubMed

Ribelles N, Santonja A, Pajares B, Llacer C, Alba E. The seed and soil hypothesis revisited: current state of knowledge of inherited genes on prognosis in breast cancer. Cancer Treat Rev. 2014;40(2):293–9. doi:10.1016/j.ctrv.2013.09.010.CrossRefPubMed

Kakonen SM, Mundy GR. Mechanisms of osteolytic bone metastases in breast carcinoma. Cancer. 2003;97(3 Suppl):834–9. doi:10.1002/cncr.11132.CrossRefPubMed

Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27(3):165–76. doi:10.1053/ctrv.2000.0210.CrossRefPubMed

Martin TJ, Suva LJ. Parathyroid hormone-related protein: a novel gene product. Baillieres Clin Endocrinol Metab. 1988;2(4):1003–29.CrossRefPubMed

Mangin M, Ikeda K, Dreyer BE, Broadus AE. Isolation and characterization of the human parathyroid hormone-like peptide gene. Proc Natl Acad Sci U S A. 1989;86(7):2408–12.CrossRefPubMedPubMedCentral

Miao D, He B, Karaplis AC, Goltzman D. Parathyroid hormone is essential for normal fetal bone formation. J Clin Invest. 2002;109(9):1173–82. doi:10.1172/JCI14817.CrossRefPubMedPubMedCentral

Wysolmerski JJ, Cormier S, Philbrick WM, Dann P, Zhang JP, Roume J, et al. Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab. 2001;86(4):1788–94. doi:10.1210/jcem.86.4.7404.PubMed

10.

Philbrick WM. Parathyroid hormone-related protein is a developmental regulatory molecule. Eur J Oral Sci. 1998;106 Suppl 1:32–7.CrossRefPubMed

11.

Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC. Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol. 1994;126(6):1611–23.CrossRefPubMed

12.

Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature. 2014;513(7516):100–4. doi:10.1038/nature13528.CrossRefPubMedPubMedCentral

13.

Urosevic J, Garcia-Albeniz X, Planet E, Real S, Cespedes MV, Guiu M, et al. Colon cancer cells colonize the lung from established liver metastases through p38 MAPK signalling and PTHLH. Nat Cell Biol. 2014;16(7):685–94. doi:10.1038/ncb2977.CrossRefPubMed

14.

Mula RV, Bhatia V, Falzon M. PTHrP promotes colon cancer cell migration and invasion in an integrin alpha6beta4-dependent manner through activation of Rac1. Cancer Lett. 2010;298(1):119–27. doi:10.1016/j.canlet.2010.06.009.CrossRefPubMedPubMedCentral

15.

Montgrain PR, Deftos LJ, Arenberg D, Tipps A, Quintana R, Carskadon S, et al. Prognostic implications of parathyroid hormone-related protein in males and females with non--small-cell lung cancer. Clin Lung Cancer. 2011;12(3):197–205. doi:10.1016/j.cllc.2011.03.018.CrossRefPubMed

16.

Liao J, Li X, Koh AJ, Berry JE, Thudi N, Rosol TJ, et al. Tumor expressed PTHrP facilitates prostate cancer-induced osteoblastic lesions. Int J Cancer. 2008;123(10):2267–78. doi:10.1002/ijc.23602.CrossRefPubMedPubMedCentral

17.

Downs TM, Burton DW, Araiza FL, Hastings RH, Deftos LJ. PTHrP stimulates prostate cancer cell growth and upregulates aldo-keto reductase 1C3. Cancer Lett. 2011;306(1):52–9. doi:10.1016/j.canlet.2011.02.027.CrossRefPubMed

18.

Cafforio P, Savonarola A, Stucci S, De Matteo M, Tucci M, Brunetti AE, et al. PTHrP produced by myeloma plasma cells regulates their survival and pro-osteoclast activity for bone disease progression. J Bone Miner Res. 2014;29(1):55–66. doi:10.1002/jbmr.2022.CrossRefPubMed

19.

Guise TA. Parathyroid hormone-related protein and bone metastases. Cancer. 1997;80(8 Suppl):1572–80.CrossRefPubMed

20.

Akhtari M, Mansuri J, Newman KA, Guise TM, Seth P. Biology of breast cancer bone metastasis. Cancer Biol Ther. 2008;7(1):3–9.CrossRefPubMed

21.

Li J, Karaplis AC, Huang DC, Siegel PM, Camirand A, Yang XF, et al. PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target. J Clin Invest. 2011;121(12):4655–69. doi:10.1172/JCI46134.CrossRefPubMedPubMedCentral

22.

Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983;258(11):7155–60.PubMed

23.

Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000;342(18):1350–8. doi:10.1056/NEJM200005043421807.CrossRefPubMed

24.

Kim IY, Kim MM, Kim SJ. Transforming growth factor-beta : biology and clinical relevance. J Biochem Mol Biol. 2005;38(1):1–8.CrossRefPubMed

25.

Massague J. TGFbeta in Cancer. Cell. 2008;134(2):215–30. doi:10.1016/j.cell.2008.07.001.CrossRefPubMedPubMedCentral

26.

Padua D, Massague J. Roles of TGFbeta in metastasis. Cell Res. 2009;19(1):89–102. doi:10.1038/cr.2008.316.CrossRefPubMed

27.

Donovan J, Slingerland J. Transforming growth factor-beta and breast cancer: Cell cycle arrest by transforming growth factor-beta and its disruption in cancer. Breast Cancer Res. 2000;2(2):116–24.CrossRefPubMedPubMedCentral

28.

Dumont N, Arteaga CL. Transforming growth factor-beta and breast cancer: Tumor promoting effects of transforming growth factor-beta. Breast Cancer Res. 2000;2(2):125–32.CrossRefPubMedPubMedCentral

29.

Kretzschmar M. Transforming growth factor-beta and breast cancer: Transforming growth factor-beta/SMAD signaling defects and cancer. Breast Cancer Res. 2000;2(2):107–15.CrossRefPubMedPubMedCentral

30.

Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. 2012;44(3):312–8. doi:10.1038/ng.1049.CrossRefPubMedPubMedCentral

31.

Linforth R, Anderson N, Hoey R, Nolan T, Downey S, Brady G, et al. Coexpression of parathyroid hormone related protein and its receptor in early breast cancer predicts poor patient survival. Clin Cancer Res. 2002;8(10):3172–7.PubMed

32.

Kissin MW, Henderson MA, Danks JA, Hayman JA, Bennett RC, Martin TJ. Parathyroid hormone related protein in breast cancers of widely varying prognosis. Eur J Surg Oncol. 1993;19(2):134–42.PubMed

33.

Surowiak P, Dziegiel P, Matkowski R, Sopel M, Wojnar A, Kornafel J, et al. Prognostic value of immunocytochemical determination of parathyroid hormone-related peptide expression in cells of mammary ductal carcinoma. Analysis of 7 years of the disease course. Virchows Arch. 2003;442(3):245–51. doi:10.1007/s00428-002-0743-5.PubMed

34.

Henderson MA, Danks JA, Slavin JL, Byrnes GB, Choong PF, Spillane JB, et al. Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Res. 2006;66(4):2250–6. doi:10.1158/0008-5472.CAN-05-2814.CrossRefPubMed

35.

Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700.CrossRefPubMed

36.

Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7(10):1118–22. doi:10.1038/nm1001-1118.CrossRefPubMed

37.

Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8(5):369–80. doi:10.1016/j.ccr.2005.10.012.CrossRefPubMed

38.

Petersen M, Pardali E, van der Horst G, Cheung H, van den Hoogen C, van der Pluijm G, et al. Smad2 and Smad3 have opposing roles in breast cancer bone metastasis by differentially affecting tumor angiogenesis. Oncogene. 2010;29(9):1351–61. doi:10.1038/onc.2009.426.CrossRefPubMed

39.

Wilson TJ, Nannuru KC, Futakuchi M, Singh RK. Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1. Cancer Lett. 2010;288(2):162–9. doi:10.1016/j.canlet.2009.06.035.CrossRefPubMed

40.

Papageorgis P, Lambert AW, Ozturk S, Gao F, Pan H, Manne U, et al. Smad signaling is required to maintain epigenetic silencing during breast cancer progression. Cancer Res. 2010;70(3):968–78. doi:10.1158/0008-5472.CAN-09-1872.CrossRefPubMedPubMedCentral

41.

Vendrell JA, Thollet A, Nguyen NT, Ghayad SE, Vinot S, Bieche I, et al. ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion. Cancer Res. 2012;72(14):3593–606. doi:10.1158/0008-5472.CAN-11-3095.CrossRefPubMed

42.

Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2):156–72. doi:10.1038/cr.2009.5.CrossRefPubMedPubMedCentral

43.

Wang Y, Lei R, Zhuang X, Zhang N, Pan H, Li G, et al. DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis. J Clin Invest. 2014;124(4):1646–59. doi:10.1172/JCI71812.CrossRefPubMedPubMedCentral

44.

Zhang Y, Ma B, Fan Q. Mechanisms of breast cancer bone metastasis. Cancer Lett. 2010;292(1):1–7. doi:10.1016/j.canlet.2009.11.003.CrossRefPubMed

45.

Zheng L, Zhu K, Jiao H, Zhao Z, Zhang L, Liu M, et al. PTHrP expression in human MDA-MB-231 breast cancer cells is critical for tumor growth and survival and osteoblast inhibition. Int J Biol Sci. 2013;9(8):830–41. doi:10.7150/ijbs.7039.CrossRefPubMedPubMedCentral

46.

Agouni A, Sourbier C, Danilin S, Rothhut S, Lindner V, Jacqmin D, et al. 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. 2007;28(9):1893–901. doi:10.1093/carcin/bgm106.CrossRefPubMed

47.

Gessi M, Monego G, Calviello G, Lanza P, Giangaspero F, Silvestrini A, et al. Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines. Acta Neuropathol. 2007;114(2):135–45. doi:10.1007/s00401-007-0212-y.CrossRefPubMed

48.

Hastings RH, Montgrain PR, Quintana R, Rascon Y, Deftos LJ, Healy E. Cell cycle actions of parathyroid hormone-related protein in non-small cell lung carcinoma. Am J Physiol Lung Cell Mol Physiol. 2009;297(4):L578–85. doi:10.1152/ajplung.90560.2008.CrossRefPubMedPubMedCentral

49.

Gagiannis S, Muller M, Uhlemann S, Koch A, Melino G, Krammer PH, et al. Parathyroid hormone-related protein confers chemoresistance by blocking apoptosis signaling via death receptors and mitochondria. Int J Cancer. 2009;125(7):1551–7. doi:10.1002/ijc.24471.CrossRefPubMed

50.

Mak IW, Cowan RW, Turcotte RE, Singh G, Ghert M. PTHrP induces autocrine/paracrine proliferation of bone tumor cells through inhibition of apoptosis. PLoS One. 2011;6(5), e19975. doi:10.1371/journal.pone.0019975.CrossRefPubMedPubMedCentral

51.

Mak IW, Turcotte RE, Ghert M. Parathyroid hormone-related protein (PTHrP) modulates adhesion, migration and invasion in bone tumor cells. Bone. 2013;55(1):198–207. doi:10.1016/j.bone.2013.02.020.CrossRefPubMed

52.

Washam CL, Byrum SD, Leitzel K, Ali SM, Tackett AJ, Gaddy D, et al. Identification of PTHrP(12–48) as a plasma biomarker associated with breast cancer bone metastasis. Cancer Epidemiol Biomarkers Prev. 2013;22(5):972–83. doi:10.1158/1055-9965.EPI-12-1318-T.CrossRefPubMedPubMedCentral

53.

Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350(16):1655–64. doi:10.1056/NEJMra030831.CrossRefPubMed

54.

Kremer R, Karaplis AC, Henderson J, Gulliver W, Banville D, Hendy GN, et al. 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;87(3):884–93. doi:10.1172/JCI115094.CrossRefPubMedPubMedCentral

55.

Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584–93. doi:10.1038/nrc867.CrossRefPubMed

56.

Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7(9):659–72. doi:10.1038/nrc2193.CrossRefPubMed

57.

Wright LE, Frye JB, Lukefahr AL, Timmermann BN, Mohammad KS, Guise TA, et al. Curcuminoids block TGF-beta signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis. J Nat Prod. 2013;76(3):316–21. doi:10.1021/np300663v.CrossRefPubMed

58.

Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med. 2002;347(20):1593–603. doi:10.1056/NEJMra021902.CrossRefPubMed

Title: Co-expression of parathyroid hormone related protein and TGF-beta in breast cancer predicts poor survival outcome
Authors: Cheng Xu
Zhengyuan Wang
Rongrong Cui
Hongyu He
Xiaoyan Lin
Yuan Sheng
Hongwei Zhang
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-015-1873-x

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