Breast Cancer Research and Treatment

, Volume 78, Issue 2, pp 149–158 | Cite as

The Prognostic Value of the Human Kallikrein Gene 9 (KLK9) in Breast Cancer

  • George M. Yousef
  • Andreas Scorilas
  • Terukazu Nakamura
  • Mohamed Abd Ellatif
  • Riccardo Ponzone
  • Nicoletta Biglia
  • Furio Maggiorotto
  • Riccardo Roagna
  • Piero Sismondi
  • Eleftherios P. Diamandis
Article

Abstract

Background. Many members of the human kallikrein gene family were found to be differentially expressed in various malignancies and some of them are useful diagnostic/prognostic markers. KLK9 is a newly discovered human kallikrein gene that is expressed in several tissues including thymus, spinal cord, testis, prostate, breast, and ovary. Like other kallikreins, the KLK9 gene was found to be regulated by steroid hormones, mainly estrogens and progestins, in cancer cell lines.

Experimental design. We studied the expression of KLK9 by quantitative RT-PCR in 169 breast cancer patients of different stages, grades and histological types. We also compared the relation between KLK9 expression and other clinicopathological variables and patient survival.

Results.KLK9 expression is significantly higher in patients with early stage cancers (p = 0.039) and in patients with small tumor size (<2 cm) (p = 0.028). Kaplan-Meier survival curves demonstrated that KLK9-positive patients have longer disease-free and overall survival (p = 0.015 and 0.036, respectively). Univariate and multivariate analysis also indicates that KLK9 expression is associated with increased disease-free and overall survival. When the Cox proportional hazard regression analysis was applied to subgroups of patients, KLK9 expression was found to be a significant predictor of disease-free survival in the estrogen receptor (ER) and progesterone receptor (PR) negative subgroups of patients (Hazard Ratio 'HR' = 0.28, and 0.38, respectively, and p = 0.011 and 0.028, respectively). After adjusting for other known prognostic variables, KLK9 retained its independent prognostic value in these subgroups of patients. Similar results were obtained for overall survival.

Conclusions.KLK9 is a new potential independent marker of favorable prognosis in breast cancer.

breast cancer cancer genes cancer predictive markers kallikreins KLK9 prognostic markers PSA serine proteases tumor markers 

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References

  1. 1.
    Hulka BS, Stark AT: Breast cancer: cause and prevention. Lancet 346: 883-887, 1995Google Scholar
  2. 2.
    Hamilton A, Piccart: The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2. Ann Oncol 11: 647-663, 2000Google Scholar
  3. 3.
    Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, Ruby SG, O'Malley F, Simpson JF, Connolly JL, Hayes DF, Edge SB, Lichter A, Schnitt SJ: Prognostic factors in breast cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124: 966-978, 2000Google Scholar
  4. 4.
    ASCO: 1997 update of recommendations for the use of tumor markers in breast and colorectal cancer. Adopted on November 7, 1997 by the American Society of Clinical Oncology. J Clin Oncol 16: 793-795, 1998Google Scholar
  5. 5.
    Schnitt SJ: Traditional and new pathologic factors. J Natl Cancer I 30: 22-26, 2001Google Scholar
  6. 6.
    Look ML, van Putten WLJ, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Ferno M, Eppenberger-Castori S, Sweep CGJF, Ulm K, Peyrat J-P, Martin P-M, Magdelenat H, Brunner N, Duggan C, Lisboa BW, Bendahl O-P, Quiiillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WF, Blankenstein MA, Broet P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LVAM, Klijn JGM, O'Higgins N, Eppenberger U, Janicke F, Schmitt M, Foekens JA: Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer I 94: 116-128, 2002Google Scholar
  7. 7.
    Smith TJ, Davidson NE, Schapira DV, Grunfeld E, Muss HB, Vogel 3rd VG, Somerfield MR: American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 17: 1080-1082, 1999Google Scholar
  8. 8.
    Yousef GM, Obiezu CV, Luo LY, Black MH, Diamandis EP: Prostase/KLK-L1 is a new member of the human kallikrein gene family, is expressed in prostate and breast tissues, and is hormonally regulated. Cancer Res 59: 4252-4256, 1999Google Scholar
  9. 9.
    Yousef GM, Diamandis EP: The new kallikrein-like gene, KLK-L2. Molecular characterization, mapping, tissue expression, and hormonal regulation. J Biol Chem 274: 37511-37516, 1999Google Scholar
  10. 10.
    Yousef GM, Diamandis EP: The expanded human kallikrein gene family: locus characterization and molecular cloning of a new member, KLK-L3 (KLK9). Genomics 65: 184-194, 2000Google Scholar
  11. 11.
    Yousef GM, Chang A, Diamandis EP: Identification and characterization of KLK-L4, a new kallikrein-like gene that appears to be down-regulated in breast cancer tissues. J Biol Chem 275: 11891-11898, 2000Google Scholar
  12. 12.
    Yousef GM, Magklara A, Diamandis EP: KLK12 is a novel serine protease and a new member of the human kallikrein gene family-differential expression in breast cancer. Genomics 69: 331-341, 2000Google Scholar
  13. 13.
    Yousef GM, Scorilas A, Jung K, Ashworth LK, Diamandis EP: Molecular cloning of the human kallikrein 15 gene (KLK15). Up-regulation in prostate cancer. J Biol Chem 276: 53-61, 2001Google Scholar
  14. 14.
    Yousef GM, Magklara A, Chang A, Jung K, Katsaros D, Diamandis EP: Cloning of a new member of the human kallikrein gene family, KLK14, which is down-regulated in different malignancies. Cancer Res 61: 3425-3431, 2001Google Scholar
  15. 15.
    Anisowicz A, Sotiropoulou G, Stenman G, Mok SC, Sager R: A novel protease homolog differentially expressed in breast and ovarian cancer. Mol Med 2: 624-636, 1996Google Scholar
  16. 16.
    Liu XL, Wazer DE, Watanabe K, Band V: Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res 56: 3371-3379, 1996Google Scholar
  17. 17.
    Yoshida S, Taniguchi M, Hirata A, Shiosaka S: Sequence analysis and expression of human neuropsin cDNA and gene. Gene 213: 9-16, 1998Google Scholar
  18. 18.
    Yousef GM, Diamandis EP: The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 22: 184-204, 2001Google Scholar
  19. 19.
    Diamandis EP, Yousef GM, Luo LY, Magklara A, Obiezu CV: The new human kallikrein gene family: implications in Carcinogenesis. Trends Endocrin Met 11: 54-60, 2000Google Scholar
  20. 20.
    Diamandis EP, Yousef GM: Human tissue kallikrein gene family: a rich source of novel disease biomarkers. Expert Rev Mol Diagn 1: 182-190, 2001Google Scholar
  21. 21.
    Diamandis EP: Prostate-specific antigen-its usefulness in clinical medicine. Trends Endocrin Met 9: 310-316, 1998Google Scholar
  22. 22.
    Stenman, UH: New ultrasensitive assays facilitate studies on the role of human glandular kallikrein (hK2) as a marker for prostatic disease. Clin Chem 45: 753-754, 1999Google Scholar
  23. 23.
    Partin, AW, Catalona WJ, Finlay JA, Darte C, Tindall DJ, Young CY, Klee GG, Chan DW, Rittenhouse HG, Wolfert RL, Woodrum DL: Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis. Urology 54: 839-845, 1999Google Scholar
  24. 24.
    Yu H, Giai M, Diamandis EP, Katsaros D, Sutherland DJ, Levesque MA, Roagna R, Ponzone R, Sismondi P: Prostatespecific antigen is a new favorable prognostic indicator for women with breast cancer. Cancer Res 55: 2104-2110, 1995Google Scholar
  25. 25.
    Goyal J, Smith KM, Cowan JM, Wazer DE, Lee SW, Band V: The role for NES1 serine protease as a novel tumor suppressor. Cancer Res 58: 4782-4786, 1998Google Scholar
  26. 26.
    Yousef GM, Kyriakopoulou LG, Scorilas A, Fracchioli S, Ghiringhello B, Zarghooni M, Chang A, Diamandis M, Giardina G, Hartwick WJ, Richiardi G, Massobrio M, Diamandis EP, Katsaros D: Quantitative expression of the human kallikrein gene 9 (KLK9) in ovarian cancer: a new independent and favorable prognostic marker. Cancer Res 61: 7811-7818, 2001Google Scholar
  27. 27.
    Bloom HJG, Richardson WW: Histological grading and prognosis in breast cancer. Br J Cancer 11: 359-377, 1957Google Scholar
  28. 28.
    EORTC: Revision of the standards for the assessment of hormone receptors in human breast cancer; report of the second E.O.R.T.C. Workshop, held on 16-17 March 1979, in the Netherlands Cancer Institute. Eur J Cancer 16: 1513-1515, 1980Google Scholar
  29. 29.
    Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-202, 1972Google Scholar
  30. 30.
    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958Google Scholar
  31. 31.
    Yousef GM, Scorilas A, Kyriakopoulou LG, Rendl L, Diamandis M, Ponzone R, Biglia N, Giai M, Roagna R, Sismondi P, Diamandis EP: Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer. Clin Chem 2002 (in Press)Google Scholar
  32. 32.
    Chang A, Yousef GM, Scorilas A, Grass L, Sismondi P, Ponzone R, Diamandis EP: Human kallikrein gene 13 (KLK13) expression by quantitative RT-PCR: an independent indicator of favorable prognosis in breast cancer. Br J Cancer 2002 (in Press)Google Scholar
  33. 33.
    Li B, Goyal J, Dhar S, Dimri G, Evron E, Sukumar S, Wazer DE, Band V: CpG methylation as a basis for breast tumorspecific loss of NES1/kallikrein 10 expression. Cancer Res 61: 8014-8021, 2001Google Scholar
  34. 34.
    Dhar S, Bhargava R, Yunes M, Li B, Goyal J, Naber SP, Wazer DE, Band V: Analysis of normal epithelial cell specific-1 (NES1)/Kallikrein 10 mRNA expression by in situ hybridization, a novel marker for breast cancer. Clin Cancer Res 7: 3393-3398, 2001Google Scholar
  35. 35.
    Birrell SN, Hall RE, Tilley WD: Role of the androgen receptor in human breast cancer. J Mammary Gland Biol 3: 95-103, 1998Google Scholar
  36. 36.
    Russo IH, Russo J: Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol 3: 49-61, 1998Google Scholar
  37. 37.
    Fortier AH, Nelson BJ, Grella DK, Holaday JW: Antiangiogenic activity of prostate-specific antigen. J Natl Cancer I 91: 1635-1640, 1999Google Scholar
  38. 38.
    Lai LC, Erbas H, Lennard TW, Peaston RT: Prostate-specific antigen in breast cyst fluid: possible role of prostate-specific antigen in hormone-dependent breast cancer. Int J Cancer 66: 743-746, 1996Google Scholar
  39. 39.
    Diamandis, EP: Prostate-specific antigen: a cancer fighter and a valuable messenger? Clin Chem 46: 896-900, 2000Google Scholar
  40. 40.
    Clark GM, Hilsenbeck SG, Ravdin PM, De Laurentiis M, Osborne CK: Prognostic factors: rationale and methods of analysis and integration. Breast Cancer Res Tr 32: 105-112, 1994Google Scholar
  41. 41.
    De Laurentiis M, De Placido S, Bianco AR, Clark GM, Ravdin PM: A prognostic model that makes quantitative estimates of probability of relapse for breast cancer patients. Clin Cancer Res 5: 4133-4139, 1999Google Scholar
  42. 42.
    Yousef GM, Diamandis EP: Human kallikreins: common structural features, sequence analysis and evolution. Current Genomics 2002 (in Press)Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • George M. Yousef
    • 1
    • 2
  • Andreas Scorilas
    • 3
  • Terukazu Nakamura
    • 1
  • Mohamed Abd Ellatif
    • 4
  • Riccardo Ponzone
    • 5
  • Nicoletta Biglia
    • 5
  • Furio Maggiorotto
    • 5
  • Riccardo Roagna
    • 5
  • Piero Sismondi
    • 5
  • Eleftherios P. Diamandis
    • 1
    • 2
  1. 1.Department of Pathology and Laboratory Medicine, Mount Sinai HospitalUniversity of TorontoTorontoCanada
  2. 2.University of TorontoTorontoCanada
  3. 3.National Center of Scientific Research 'Demokritos'IPCAthensGreece
  4. 4.Department of BiochemistryMansura UniversityEgypt
  5. 5.Academic Division of Gynecological OncologyUniversity of Turin, Mauriziano Umberto I° Hospital and Institute for Cancer Research and Treatment (IRCC) of CandioloTurinItaly

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