Abstract
Our laboratory is involved in identifying genes that can be used as early diagnostic or prognostic markers in breast cancer. We previously identified a gene (NES1) that is expressed in normal but not in transformed mammary epithelial cells (MECs). NES1 is located on chromosome 19q13.4 within the kallikrein locus and thus was designated as human kallikrein 10 (hK10), although we have been unable to detect any protease activity. Importantly, hK10 expression is decreased in a majority of breast cancer cell lines. Transfection of hK10 into hK10-negative breast cancer cells reduces the tumorigenicity. Using methylation-specific PCR and subsequent sequencing, we demonstrate a strong correlation between hypermethylation of hK10 and loss of mRNA expression. Further analysis showed that essentially 100% of normal breast specimens had hK10 expression, whereas 46% of ductal carcinoma in situ (DCIS) and the majority of infiltrating ductal carcinoma (IDC) samples lacked the hK10 mRNA. Importantly, hK10-negative DCIS diagnosed at the time of biopsy were subsequently diagnosed as IDC at the time of definitive surgery. It has been shown that hK10 protein expression is regulated by steroids. In addition to breast cancers, hK10 is downregulated in cervical cancer, prostate cancer and acute lymphocytic leukemia, whereas it is upregulated in ovarian cancers. These results point to the paradoxical role of hK10 in human cancers and underscore the importance of further studies of this kallikrein.
References
American Cancer Society (2005). Breast Cancer Facts and Figures 2005 (www.cancer.org/docroot/STT/stt_0_2005.asp?sitearea=STT&level=1).Search in Google Scholar
Astrom, A., Pettersson, U., Chambon, P., and Voorhees, J.J. (1994). Retinoic acid induction of human cellular retinoic acid-binding protein-II gene transcription is mediated by retinoic acid receptor-retinoid X receptor heterodimers bound to one far upstream retinoic acid-responsive element with 5-base pair spacing. J. Biol. Chem.269, 22334–22339.10.1016/S0021-9258(17)31794-5Search in Google Scholar
Bharaj, B.B., Luo, L.Y., Jung, K., Stephan, C., and Diamandis, E.P. (2002). Identification of single nucleotide polymorphisms in the human kallikrein 10 (KLK10) gene and their association with prostate, breast, testicular, and ovarian cancers. Prostate51, 35–41.10.1002/pros.10076Search in Google Scholar
Bast, R.C. Jr., Ravdin, P., Hayes, D.F., Bates, S., Fritsche H. Jr., Jessup, J.M., Kemeny, N., Locker, G.Y., Mennel, R.G., and Somerfield, M.R. (2001). 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J. Clin. Oncol.19, 1865–1878.10.1200/JCO.2001.19.6.1865Search in Google Scholar
Cleutjens, K.B., van der Korput, H.A., van Eekelen, C.C., van Rooij, H.C., Faber, P.W., and Trapman, J. (1997). An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol. Endocrinol.11, 148–161.10.1210/mend.11.2.9883Search in Google Scholar
Coradini, D. and Daidone, M.G. (2004). Biomolecular prognostic factors in breast cancer. Curr. Opin. Obstet. Gynecol.16, 49–55.10.1097/00001703-200402000-00010Search in Google Scholar
Dhar, S., Bhargava, R., Yunes, M., Li, B., Goyal, J., Naber, S.P., Wazer, D.E., and Band, V. (2001). 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.Search in Google Scholar
Dimri, G., Band, H., and Band, V. (2005). Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res.7, 171–179.10.1186/bcr1275Search in Google Scholar
Goyal, J., Smith, K.M., Cowan, J.M., Wazer, D.E., Lee, S.W., and Band, V. (1998). The role for NES1 serine protease as a novel tumor suppressor. Cancer Res.58, 4782–4786.Search in Google Scholar
Li, B., Goyal, J., Dhar, S., Dimri, G., Evron, E., Sukumar, S., Wazer, D.E., and Band, V. (2001). CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression. Cancer Res.61, 8014–8021.Search in Google Scholar
Liu, X.L., Wazer, D.E., Watanabe, K., and Band, V. (1996). Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res.56, 3371–3379.Search in Google Scholar
Luo, L., Herbrick, J.A., Scherer, S.W., Beatty, B., Squire, J., and Diamandis, E.P. (1998). Structural characterization and mapping of the normal epithelial cell-specific 1 gene. Biochem. Biophys. Res. Commun.247, 580–586.10.1006/bbrc.1998.8793Search in Google Scholar
Luo, L.Y., Grass, L., and Diamandis, E.P. (2000). The normal epithelial cell-specific 1 (NES1) gene is up-regulated by steroid hormones in the breast carcinoma cell line BT-474. Anticancer Res.20, 981–986.Search in Google Scholar
Luo, L.Y., Grass, L., Howarth, D.J., Thibault, P., Ong, H., and Diamandis, E.P. (2001a). Immunofluorometric assay of human kallikrein 10 and its identification in biological fluids and tissues. Clin. Chem.47, 237–246.10.1093/clinchem/47.2.237Search in Google Scholar
Luo, L.Y., Rajpert-De Meyts, E.R., Jung, K., and Diamandis, E.P. (2001b). Expression of the normal epithelial cell-specific 1 (NES1; KLK10) candidate tumour suppressor gene in normal and malignant testicular tissue. Br. J. Cancer85, 220–224.10.1054/bjoc.2001.1870Search in Google Scholar
Luo, L.Y., Bunting, P., Scorilas, A., and Diamandis, E.P. (2001c). Human kallikrein 10: a novel tumor marker for ovarian carcinoma? Clin. Chim. Acta6, 111–118.10.1016/S0009-8981(01)00401-6Search in Google Scholar
Luo, L.Y., Katsaros, D., Scorilas, A., Fracchioli, S., Piccinno, R., Rigault de la Longrais, I.A., Howarth, D.J., and Diamandis, E.P. (2001d). Prognostic value of human kallikrein 10 expression in epithelial ovarian carcinoma. Clin. Cancer Res.7, 2372–2379.Search in Google Scholar
Luo, L.Y., Grass, L., and Diamandis, E.P. (2003a). Steroid hormone regulation of the human kallikrein 10 (KLK10) gene in cancer cell lines and functional characterization of the KLK10 gene promoter. Clin. Chim. Acta337, 115–126.10.1016/j.cccn.2003.07.008Search in Google Scholar
Luo, L.Y., Katsaros, D., Scorilas, A., Fracchioli, S., Bellino, R., van Gramberen, M., de Bruijn, H., Henrik, A., Stenman, U.H., Massobrio, M., et al. (2003b). The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Cancer Res.63, 807–811.Search in Google Scholar
Magklara, A., Brown, T.J., and Diamandis, E.P. (2002). Characterization of androgen receptor and nuclear receptor co-regulator expression in human breast cancer cell lines exhibiting differential regulation of kallikreins 2 and 3. Int. J. Cancer100, 507–514.10.1002/ijc.10520Search in Google Scholar
Mielnicki, L.M., Asch, H.L., and Asch, B.B. (2001). Genes, chromatin, and breast cancer: an epigenetic tale. J. Mammary Gland Biol. Neoplasia6, 169–182.10.1023/A:1011356623442Search in Google Scholar
Petraki, C.D., Karavana, V.N., Luo, L.Y., and Diamandis, E.P. (2002). Human kallikrein 10 expression in normal tissues by immunohistochemistry. J. Histochem. Cytochem.50, 1247–1261.10.1177/002215540205000912Search in Google Scholar
Ramharack, R., Wyborski, R.J., and Spahr, M.A. (1998). The apolipoprotein(a) promoter contains a retinoid response element. Biochem. Biophys. Res. Commun.245, 194–197.10.1006/bbrc.1998.8398Search in Google Scholar
Rastinejad, F. (2001). Retinoid X receptor and its partners in the nuclear receptor family. Curr. Opin. Struct. Biol.11, 33–38.10.1016/S0959-440X(00)00165-2Search in Google Scholar
Roman-Gomez. J., Jimenez-Velasco, A., Agirre, X., Castillejo, J. A., Barrios, M., Andreu, E.J., Prosper, F., Heiniger, A., and Torres, A. (2004). The normal epithelial cell-specific 1 (NES1) gene, a candidate tumor suppressor gene on chromosome 19q13.3–4, is downregulated by hypermethylation in acute lymphoblastic leukemia. Leukemia18, 362–365.Search in Google Scholar
Rosen, D.G., Wang, L., Atkinson, J.N., Yu, Y., Lu, K.H., Diamandis, E.P., Hellstrom, I., Mok, S.C., Liu, J., and Bast, R.C. Jr. (2005). Potential markers that complement expression of CA125 in epithelial ovarian cancer. Gynecol. Oncol.99, 267–277.10.1016/j.ygyno.2005.06.040Search in Google Scholar
Shvartsman, H.S., Lu, K.H., Lee, J., Lillie, J., Deavers, M.T., Clifford, S., Wolf, J.K., Mills, G.B., Bast, R.C. Jr., Gershenson, D.M., and Schmandt, R. (2003). Overexpression of kallikrein 10 in epithelial ovarian carcinomas. Gynecol. Oncol.90, 44–50.10.1016/S0090-8258(03)00257-9Search in Google Scholar
Sidiropoulos, M., Pampalakis, G., Sotiropoulou, G., Katsaros, D., and Diamandis, E.P. (2005). Downregulation of human kallikrein 10 (KLK10/NES1) by CpG island hypermethylation in breast, ovarian and prostate cancers. Tumour Biol.26, 324–336.10.1159/000089290Search in Google Scholar PubMed
Stryer, L. (1988). Biochemistry, 3rd Edition (New York, USA: W.H. Freeman & Co.).Search in Google Scholar
Wazer, D.E., Chu, Q., Liu, X.L., Gao, Q., Safaii, H., and Band, V. (1994). Loss of p53 protein during radiation transformation of primary human mammary epithelial cells. Mol. Cell. Biol.14, 2468–2478.Search in Google Scholar
Yousef, G.M., Scorilas, A., Kyriakopoulou, L.G., Rendl, L., Diamandis, M., Ponzone, R., Biglia, N., Giai, M., Roagna, R., Sismondi, P., and Diamandis, E.P. (2002). Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer. Clin. Chem.48, 1241–1250.10.1093/clinchem/48.8.1241Search in Google Scholar
Yousef, G.M., Scorilas, A., Katsaros, D., Fracchioli, S., Iskander, L., Borgono, C., Rigault de la Longrais, I.A., Puopolo, M., Massobrio, M., and Diamandis, E.P. (2003). Prognostic value of the human kallikrein gene 15 expression in ovarian cancer. J. Clin. Oncol.21, 3119–3126.10.1200/JCO.2003.09.111Search in Google Scholar
Yousef, G.M., Obiezu, C.V., Luo, L.Y., Magklara, A., Borgono, C.A., Kishi, T., Memari, N., Michael, P., Sidiropoulos, M., Kurlender, L., et al. (2005). Human tissue kallikreins: from gene structure to function and clinical applications. Adv. Clin. Chem.39, 11–79.10.1016/S0065-2423(04)39002-5Search in Google Scholar
Yunes, M.J., Neuschatz, A.C., Bornstein, L.E., Naber, S.P., Band, V., and Wazer, D.E. (2003). Loss of expression of the putative tumor suppressor NES1 gene in biopsy-proven ductal carcinoma in situ predicts for invasive carcinoma at definitive surgery. Int. J. Radiat. Oncol. Biol. Phys.56, 653–657.10.1016/S0360-3016(03)00068-3Search in Google Scholar
Zeng, M., Zhang, Y., Bhat, I., Wazer, D., and Band, V. (2006). The human kallikrein 10 promoter contains a functional retinoid response element. Biol. Chem.387, 741–747.10.1515/BC.2006.093Search in Google Scholar PubMed
©2006 by Walter de Gruyter Berlin New York
