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Coordinated steroid hormone-dependent and independent expression of multiple kallikreins in breast cancer cell lines

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Abstract

The regulation of gene expression by steroid hormones plays an important role in the normal development and function of many organs, as well in the pathogenesis of endocrine-related cancers. Previous experiments have shown that many kallikrein genes are under steroid hormone regulation in breast cancer cell lines. We here examine the coordinated expression of multiple kallikrein genes in several breast cancer cell lines after steroid hormone stimulation. Breast cancer cell lines were treated with various steroid hormones and kallikrein (KLK/hK) expression of hK3 (prostate-specific antigen, PSA), hK5, hK6, hK7, hK8, hK10, hK11, hK13, and hK14 was analyzed at the RNA level via RT-PCR and at the protein level by immunofluorometric ELISA assays. We identified several distinct hK hormone-dependent and hormone-independent expression patterns. Hormone-specific modulation of expression was seen for several kallikreins in BT-474, MCF-7, and T-47D cell lines. hK6 was specifically up-regulated upon estradiol treatment in all three cell lines whereas PSA expression was induced by dihydrotestosterone (DHT) and norgestrel stimulation in BT-474 and T-47D. hK10, hK11, hK13, and hK14 were specifically up-regulated by DHT in T-47D and by estradiol in BT-474 cells. Bioinformatic analysis of upstream proximal promoter sequences for these hKs did not identify any recognizable hormone-response elements (HREs), suggesting that the coordinated activation of these four hKs represents a unique expression “cassette”, utilizing a common hormone-dependent mechanism. We conclude that groups of human hKs are coordinately expressed in a steroid hormone-dependent manner. Our data supports clinical observations linking expression of multiple hKs with breast cancer prognosis.

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Abbreviations

KLK:

Kallikrein gene

HK:

Kallikrein protein

HRE:

Hormone-response element

ELISA:

Enzyme-linked immunosorbent assay

PSA:

Prostate-specific antigen

AR:

Androgen receptor

PR:

Progesterone receptor

ER:

Estrogen receptor; bp, base pair

DHT:

Dihydrotestosterone

DFP:

Difunisal phosphate

ECM:

Extracellular matrix

IGF:

Insulin-like growth factor

IGFBP:

Insulin-like growth factor binding protein

FBS:

Fetal bovine serum

References

  1. Diamandis EP, Yousef GM, Clements J et al (2000) New nomenclature for the human tissue kallikrein gene family. Clin Chem 46:1855–1858

    PubMed  CAS  Google Scholar 

  2. Butt AJ, McNeil CM, Musgrove EA et al (2005) Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E. Endocr Relat Cancer 12(Suppl 1):S47–S59

    Article  PubMed  CAS  Google Scholar 

  3. Borgono CA, Diamandis EP (2004) The emerging roles of human tissue kallikreins in cancer. Nat Rev Cancer 4:876–890

    Article  PubMed  CAS  Google Scholar 

  4. Borgono CA, Michael IP, Diamandis EP (2004) Human tissue kallikreins: physiologic roles and applications in cancer. Mol Cancer Res 2:257–280

    PubMed  CAS  Google Scholar 

  5. Aranda A, Pascual A (2001) Nuclear hormone receptors and gene expression. Physiol Rev 81:1269–1304

    PubMed  CAS  Google Scholar 

  6. Baniahmad A (2005) Nuclear hormone receptor co-repressors. J Steroid Biochem Mol Biol 93:89–97

    Article  PubMed  CAS  Google Scholar 

  7. Moehren U, Eckey M, Baniahmad A (2004) Gene repression by nuclear hormone receptors. Essays Biochem 40:89–104

    PubMed  CAS  Google Scholar 

  8. Riegman PH, Vlietstra RJ, van der Korput JA et al (1991) The promoter of the prostate-specific antigen gene contains a functional androgen responsive element. Mol Endocrinol 5:1921–1930

    PubMed  CAS  Google Scholar 

  9. Cleutjens KB, van Eekelen CC, van der Korput HA et al (1996) Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem 271:6379–6388

    Article  PubMed  CAS  Google Scholar 

  10. Schuur ER, Henderson GA, Kmetec LA et al (1996) Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 271:7043–7051

    Article  PubMed  CAS  Google Scholar 

  11. Murtha P, Tindall DJ, Young CY (1993) Androgen induction of a human prostate-specific kallikrein, hKLK2: characterization of an androgen response element in the 5′ promoter region of the gene. Biochemistry 32:6459–6464

    Article  PubMed  CAS  Google Scholar 

  12. Yu DC, Sakamoto GT, Henderson DR (1999) Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy. Cancer Res 59:1498–1504

    PubMed  CAS  Google Scholar 

  13. Magklara A, Grass L, Diamandis EP (2000) Differential steroid hormone regulation of human glandular kallikrein (hK2) and prostate-specific antigen (PSA) in breast cancer cell lines. Breast Cancer Res Treat 59:263–270

    Article  PubMed  CAS  Google Scholar 

  14. Nelson PS, Gan L, Ferguson C et al (1999) Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression. Proc Natl Acad Sci USA 96:3114–3119

    Article  PubMed  CAS  Google Scholar 

  15. Obiezu CV, Shan SJ, Soosaipillai A et al (2005) Human kallikrein 4: quantitative study in tissues and evidence for its secretion into biological fluids. Clin Chem 51:1432–1442

    Article  PubMed  CAS  Google Scholar 

  16. Obiezu CV, Soosaipillai A, Jung K et al (2002) Detection of human kallikrein 4 in healthy and cancerous prostatic tissues by immunofluorometry and immunohistochemistry. Clin Chem 48:1232–1240

    PubMed  CAS  Google Scholar 

  17. Yousef GM, Scorilas A, Nakamura T et al (2003) The prognostic value of the human kallikrein gene 9 (KLK9) in breast cancer. Breast Cancer Res Treat 78:149–158

    Article  PubMed  CAS  Google Scholar 

  18. Yousef GM, Scorilas A, Kyriakopoulou LG et al (2002) Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer. Clin Chem 48:1241–1250

    PubMed  CAS  Google Scholar 

  19. Yousef GM, Borgono CA, Scorilas A et al (2002) Quantitative analysis of human kallikrein gene 14 expression in breast tumours indicates association with poor prognosis. Br J Cancer 87:1287–1293

    Article  PubMed  CAS  Google Scholar 

  20. Chang A, Yousef GM, Scorilas A et al (2002) Human kallikrein gene 13 (KLK13) expression by quantitative RT-PCR: an independent indicator of favourable prognosis in breast cancer. Br J Cancer 86:1457–1464

    Article  PubMed  CAS  Google Scholar 

  21. Ferguson RA, Yu H, Kalyvas M et al (1996) Ultrasensitive detection of prostate-specific antigen by a time-resolved immunofluorometric assay and the Immulite immunochemiluminescent third-generation assay: potential applications in prostate and breast cancers. Clin Chem 42:675–684

    PubMed  CAS  Google Scholar 

  22. Yousef GM, Polymeris ME, Grass L et al (2003) Human kallikrein 5: a potential novel serum biomarker for breast and ovarian cancer. Cancer Res 63:3958–3965

    PubMed  CAS  Google Scholar 

  23. Diamandis EP, Scorilas A, Fracchioli S et al (2003) Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma. J Clin Oncol 21:1035–1043

    Article  PubMed  CAS  Google Scholar 

  24. Kishi T, Soosaipillai A, Grass L et al (2004) Development of an immunofluorometric assay and quantification of human kallikrein 7 in tissue extracts and biological fluids. Clin Chem 50:709–716

    Article  PubMed  CAS  Google Scholar 

  25. Kishi T, Grass L, Soosaipillai A et al (2003) Human kallikrein 8, a novel biomarker for ovarian carcinoma. Cancer Res 63:2771–2774

    PubMed  CAS  Google Scholar 

  26. Luo LY, Grass L, Howarth DJ et al (2001) Immunofluorometric assay of human kallikrein 10 and its identification in biological fluids and tissues. Clin Chem 47:237–246

    PubMed  CAS  Google Scholar 

  27. Diamandis EP, Okui A, Mitsui S et al (2002) Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. Cancer Res 62:295–300

    PubMed  CAS  Google Scholar 

  28. Kapadia C, Chang A, Sotiropoulou G et al (2003) Human kallikrein 13: production and purification of recombinant protein and monoclonal and polyclonal antibodies, and development of a sensitive and specific immunofluorometric assay. Clin Chem 49:77–86

    Article  PubMed  CAS  Google Scholar 

  29. Borgono CA, Grass L, Soosaipillai A et al (2003) Human kallikrein 14: a new potential biomarker for ovarian and breast cancer. Cancer Res 63:9032–9041

    PubMed  CAS  Google Scholar 

  30. Luo LY, Grass L, Diamandis EP (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

    PubMed  CAS  Google Scholar 

  31. Yousef GM, Diamandis EP (1999) The new kallikrein-like gene, KLK-L2. Molecular characterization, mapping, tissue expression, and hormonal regulation. J Biol Chem 274:37,511–37,516

    Article  CAS  Google Scholar 

  32. Rehault S, Monget P, Mazerbourg S et al (2001) Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. Eur J Biochem 268:2960–2968

    Article  PubMed  CAS  Google Scholar 

  33. Cohen P, Graves HC, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG (1992) Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab 75:1046–1053

    Article  PubMed  CAS  Google Scholar 

  34. Peterson G, Barnes S (1991) Genistein inhibition of the growth of human breast cancer cells: independence from estrogen receptors and the multi-drug resistance gene. Biochem Biophys Res Commun 179:661–667

    Article  PubMed  CAS  Google Scholar 

  35. Yasui LS, Hughes A, Desombre ER (2001) Cytotoxicity of 125I-oestrogen decay in non-oestrogen receptor-expressing human breast cancer cells, MOA-231 and oestrogen receptor-expressing MCF-7 cells. Int J Radiat Biol 77:955–962

    Article  PubMed  CAS  Google Scholar 

  36. Edwards DP, Kuhnel B, Estes PA et al (1989) Human Progesterone receptor binding to mouse tumor virus deoxyribonucleic acid:dependence on hormone and nonreceptor nuclear factor(s). Mol Endocrinol 3:381–391

    Article  PubMed  CAS  Google Scholar 

  37. Craft N, Shostak Y, Carey M et al (1999) A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5:280–285

    Article  PubMed  CAS  Google Scholar 

  38. Corey E, Quinn JE, Buhler KR et al (2003) LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate 55:239–246

    Article  PubMed  CAS  Google Scholar 

  39. Oka H, Chatani Y, Kohno M et al (2005) Constitutive activation of the 41- and 43-kDa mitogen-activated protein (MAP) kinases in the progression of prostate cancer to an androgen-independent state. Int J Urol 12:899–905

    Article  PubMed  CAS  Google Scholar 

  40. Koksal IT, Dirice E, Yasar D et al (2004) The assessment of PTEN tumor suppressor gene in combination with Gleason scoring and serum PSA to evaluate progression of prostate carcinoma. Urol Oncol 22:307–312

    PubMed  CAS  Google Scholar 

  41. Obiezu CV, Diamandis EP (2005) Human tissue kallikrein gene family: applications in cancer. Cancer Lett 224:1–22

    PubMed  CAS  Google Scholar 

  42. Oikonomopoulou K, Scorilas A, Michael IP et al (2006) Kallikreins as markers of disseminated tumour cells in ovarian cancer – a pilot study. Tumour Biol 27:104–114

    Article  PubMed  CAS  Google Scholar 

  43. Luo LY, Grass L, Diamandis EP (2003) Steroid hormone regulation of the human kallikrein 10 (KLK10) gene in cancer cell lines and functional characterization of the KLK10 gene promoter. Clin Chim Acta 337:115–126

    Article  PubMed  CAS  Google Scholar 

  44. Lin HK, Yeh S, Kang HY, Chang C (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA 98:7200–7205

    Article  PubMed  CAS  Google Scholar 

  45. Rochette-Egly C (2003) Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal 15:355–366

    Article  PubMed  CAS  Google Scholar 

  46. Blok LJ, de Ruiter PE, Brinkmann AO (1998) Forskolin-induced dephosphorylation of the androgen receptor impairs ligand binding. Biochemistry 37:3850–3857

    Article  PubMed  CAS  Google Scholar 

  47. Bakin RE, Gioeli D, Sikes RA et al (2003) Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res 63:1981–1989

    PubMed  CAS  Google Scholar 

  48. Bakin RE, Gioeli D, Bissonette EA et al (2003) Attenuation of Ras signaling restores androgen sensitivity to hormone-refractory C4-2 prostate cancer cells. Cancer Res 63: 1975–1980

    PubMed  CAS  Google Scholar 

  49. DeGraffenried LA, Fulcher L, Friedrichs WE et al (2004) Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol 15:1510–1516

    Article  PubMed  CAS  Google Scholar 

  50. Nan B, Snabboon T, Unni E et al (2003) The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. J Mol Endocrinol 31:169–183

    Article  PubMed  CAS  Google Scholar 

  51. She QB, Solit D, Basso A et al (2003) Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res 9:4340–4346

    PubMed  CAS  Google Scholar 

  52. Panigrahi AR, Pinder SE, Chan SY et al (2004) The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. J Pathol 204:93–100

    Article  PubMed  CAS  Google Scholar 

  53. Felber LM, Borgono CA, Cloutier SM et al (2005) Enzymatic profiling of human kallikrein 14 using phage-display substrate technology. Biol Chem 386:291–298

    Article  PubMed  CAS  Google Scholar 

  54. Cloutier SM, Chagas JR, Mach JP et al (2002) Substrate specificity of human kallikrein 2 (hK2) as determined by phage display technology. Eur J Biochem 269:2747–2754

    Article  PubMed  CAS  Google Scholar 

  55. Michael IP, Sotiropoulou G, Pampalakis G et al (2005) Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression. J Biol Chem 280:14,628–14,635

    Article  CAS  Google Scholar 

  56. Kapadia C, Ghosh MC, Grass L et al (2004) Human kallikrein 13 involvement in extracellular matrix degradation. Biochem Biophys Res Commun 323:1084–1090

    Article  PubMed  CAS  Google Scholar 

  57. Ghosh MC, Grass L, Soosaipillai A et al (2004) Human kallikrein 6 degrades extracellular matrix proteins and may enhance the metastatic potential of tumour cells. Tumour Biol 25:193–199

    Article  PubMed  CAS  Google Scholar 

  58. Matsumura M, Bhatt AS, Andress D et al (2005) Substrates of the prostate-specific serine protease prostase/KLK4 defined by positional-scanning peptide libraries. Prostate 62:1–13

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., M5G 1X5, Toronto, ON, Canada

    Miltiadis Paliouras & Eleftherios P. Diamandis

  2. Department of Clinical Biochemistry, University Health Network and Toronto Medical Laboratories, Toronto, ON, Canada

    Eleftherios P. Diamandis

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Miltiadis Paliouras & Eleftherios P. Diamandis

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  1. Miltiadis Paliouras
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  2. Eleftherios P. Diamandis
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Correspondence to Eleftherios P. Diamandis.

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Paliouras, M., Diamandis, E.P. Coordinated steroid hormone-dependent and independent expression of multiple kallikreins in breast cancer cell lines. Breast Cancer Res Treat 102, 7–18 (2007). https://doi.org/10.1007/s10549-006-9312-y

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  • DOI: https://doi.org/10.1007/s10549-006-9312-y

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