Skip to main content
SpringerLink
Log in

Molecular pathology of breast cancer and its application to clinical management

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Breast cancer is a major cause of morbidity and mortality in women in many parts of the world. Breast carcinomas are heterogenous in their biological and clinical behaviour and a greater understanding of how they develop and progress could lead to more directed forms of screening and therapy. It is important to determine the molecular mechanisms underlying the natural history of breast cancer.

Developments in the techniques for molecular analysis have meant that they can now be applied to a large range of clinical material such as cytological preparations and fixed, embedded material, so increasing the potential for relating any molecular alterations to clinical behaviour and response to therapy.

In this review we consider recent developments in three areas of importance to breast cancer; genetic analysis — oncogenes, tumour suppressor genes, loss of heterozygosity, microsatellite instability, familial breast cancer; steroid receptors, oestrogen regulated proteins, epidermal growth factor receptor, growth factors particularly transforming growth factor beta; and cell adhesion, invasion and metastasis — E-cadherin, integrins, proteases. These are discussed in relation to potential for screening, prognosis and treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC: Induction of apoptosis in fibroblasts by c-myc protein. Cell 69: 1–20, 1992

    Google Scholar 

  2. Edwards PAW, Ward JL, Bradbury JM: Alteration of morphogenesis by the v-myc oncogene in transplants of mouse mammary gland. Oncogene 2: 407–412, 1988

    Google Scholar 

  3. Bonilla M, Ramirez M, Lopez-Cueto J, Gariglio P: In vivo amplification and rearrangements of c-myc oncogene in human breast tumours. J Natl Cancer Inst 80: 665–671, 1988

    Google Scholar 

  4. Escot C, Theillet C, Lidereau R, Spyratos F, Champeme M-H, Gest J, Callaham R: Genetic alterations of the c-myc proto-oncogene (MYC) in human breast carcinomas. Proc Natl Acad Sci USA 83: 4834–4838, 1986

    Google Scholar 

  5. Varley JM, Swallow JE, Brammar WJ, Whittaker JL, Walker RA: Alterations to either c-erbB2 (neu) or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene 1: 423–430, 1987

    Google Scholar 

  6. Berns PMJJ, Krijn JGM, Van Putten WLJ, Van Steveren IL, Portengen H, Foekens JA: C-myc amplification is a better prognostic factor than HER2/new amplification in primary breast cancer. Cancer Res 52: 1107–1113, 1992

    Google Scholar 

  7. Walker RA, Senior PV, Jones JL, Critchley DR, Varley IM: An immuno-histochemical and in-situ hybridisation study of c-myc and c-erbB-2 expression in primary breast tumours. J Pathol 158: 97–105, 1989

    Google Scholar 

  8. Locker AP, Dowle CS, Ellis IO, Elston CW, Blamey RW, Kikora K, Evan G, Robins RA: C-myc oncogene product expression and prognosis in operable breast cancer. Br J Cancer 60: 669–672, 1989

    Google Scholar 

  9. Rochlitz CF, Scott GK, Dodson JM, Liu E, Dolbaum C, Smith HS, Benz CC: Incidence of activating ras oncogene mutations associated with primary and metastatic breast cancer. Cancer Res 49: 357–360, 1989

    Google Scholar 

  10. Theillet C, Liderau R, Escot C, Hutzell P, Brunet M, Gest J, Schlom J, Callahan R: Loss of c-H-ras-l allele and aggressive human primary breast carcinomas. Cancer Res 46: 4776–4781, 1986

    Google Scholar 

  11. Ohuchi N, Thor A, Page DL, Horan Hand P, Halter S, Schlom J, Expression of the 21,000 molecular weight ras protein with a molecular weight ras protein in a spectrum of benign and malignant human mammary tissues. Cancer Res 46: 2511–2519, 1986

    Google Scholar 

  12. Clair T, Miller WR, Cho-Chung YS: Prognostic significance of the expression of a ras protein with a molecular weight of 21,000 by human breast cancer. Cancer Res 47: 5290–5293, 1986

    Google Scholar 

  13. Walker RA, Wilkinson N: p21 ras protein expression in benign and malignant human breast. J Pathol 156: 147–153, 1988

    Google Scholar 

  14. Going JJ, Anderson TJ, Wyllie AH: Ras p21 in breast tissue: associations with pathology and cellular localisation. Br J Cancer 65: 45–50, 1992

    Google Scholar 

  15. Krontiris TG, Devlin B, Karp DD, Robert JJ, Risch N: An association between the risk of cancer and mutations in the Hrasl mini-satellite locus. N Engl J Med 329: 517–523, 1993

    Google Scholar 

  16. Coussens L, Yang-Feng TL, Chen Y-CLE, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U, Levinson A, Ullrich A: Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230: 1132–1139, 1985

    Google Scholar 

  17. Slamon DJ, Clark G, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182, 1987

    Google Scholar 

  18. Zhou D, Battifora H, Yokata J, Yamamoto T, Cline MJ: Association of multiple copies of the c-erbB-2 oncogene with the spread of breast cancer. Cancer Res 47: 6123–6125, 1987

    Google Scholar 

  19. Borresen A-L, Ottestad L, Gaustad A, Andersen TI, Heikkila R, Jahnsen T, Tveit KM, Nesland JM: Amplification and protein over-expression of the neu/HER-2/c-erbB-2 proto-oncogene in human breast carcinomas: relationship to loss of gene sequences on chromosome 17, family history and prognosis. Br J Cancer 62: 585–590, 1990

    Google Scholar 

  20. Clark GM, McGuire WL: Follow-up study of HER-2/neu amplification in primary breast cancer. Cancer Res 51: 944–948, 1991

    Google Scholar 

  21. Zhou D-J, Ahuja H, Cline MJ: Proto-oncogene abnormalities in human breast cancer: c-erbB-2 amplification does not correlate with recurrence of disease. Oncogene 4: 105–108, 1989

    Google Scholar 

  22. Liu E, Thor A, He M, Barcos M, Ljung B-M, Benz C: The HER-2(c-erbB-2) oncogene is frequently amplified in in-situ carcinomas of the breast. Oncogene 7: 1027–1032, 1992

    Google Scholar 

  23. Hubbard AL, Doris CP, Thompson AM, Chetty U, Anderson TJ: Critical determination of the frequency of c-erbB-2 amplification in breast cancer. Br J Cancer 70: 434–439, 1994

    Google Scholar 

  24. Venter DJ, Tuzi NL, Kumar S, Gullick WJ: Over-expression of the c-erbB-2 oncoprotein in human breast carcinomas: immunohistological assessment correlates with gene amplification. Lancet ii: 69–72, 1987

    Google Scholar 

  25. O'Reilly SM, Barnes DM, Camplejohn RA, Bartkova J, Gregory WM, Richards MA: The relationship between c-erbB-2 expression, S-phase fraction and prognosis in breast cancer. Br J Cancer 63: 444–446, 1991

    Google Scholar 

  26. Walker RA, Gullick WJ, Varley JM: An evaluation of immunoreactivity for c-erbB-2 protein as a marker of short-term prognosis in breast cancer. Br J Cancer 60: 426–429, 1989

    Google Scholar 

  27. Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL, Altman DG: C-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 63: 434–438, 1991

    Google Scholar 

  28. Lovekin C, Ellis IO, Locker A, Robertson JFR, Bell J, Nicholson R, Gullick WJ, Elston CW, Blamey RW: C-erbB-2 oncoprotein expression and prognosis in operable breast cancer. Br J Cancer 63: 439–443, 1991

    Google Scholar 

  29. Winstanley J, Cooke T, Murray GD, Platt-Higgins A, George WD, Holt S, Mystov M, Spedding A, Barraclough BR, Rudland PS: The long-term prognostic significance of c-erbB-2 in primary breast cancer. Br J Cancer 63: 447–450, 1991

    Google Scholar 

  30. Press MF, Piek MC, Chazin VR, Hung G, Udove JJA, Markowicz M, Danyluk J, Godolphin W, Sliwkowski M, Akita R, Paterson MC, Slamon DJ: Her-2/neu expression in node negative breast cancer: direct tissue quantitation by computerized image analysis and association of over-expression with increased risk of recurrent disease. Cancer Res 53: 4960–4970, 1993

    Google Scholar 

  31. Press MF, Hung G, Godolphin W, Slamon DJ: Sensitivity of HER-2/neu antibodies in archival tissue samples: potential source of error in immuno-histochemical studies of oncogene expression. Cancer Res 54: 2771–2777, 1994

    Google Scholar 

  32. Van der Vijver MJ, Peterse JL, Mooi WJ, Wisman P, Lomans J, Dalesio O, Nuse R: Neu-protein over-expression in breast cancer: association with comedo-type ductal carcinoma in situ and limited prognostic value in Stage II breast cancer. N Engl J Med 319: 1239–1245, 1988

    Google Scholar 

  33. Bartkova J, Barnes DM, Millis RR, Gullick WJ: Immunohistochemical demonstration of c-erbB-2 protein in mammary ductal carcinoma in situ. Hum Pathol 21: 1164–1167, 1990

    Google Scholar 

  34. Ramachandra S, Machin L, Ashley S, Monaghan P, Gusterson BA: Immunohistochemical distribution of c-erbB-2 in in situ breast carcinoma — a detailed morphological analysis. J Pathol 161: 7–14, 1990

    Google Scholar 

  35. Lodata RJF, Maguire HC Jr, Greene MI, Weiner DB, LiVolsi VA: Immunohistochemical evaluation of c-erbB-2 oncogene expression in ductal carcinoma in situ and atypical ductal hyperplasia of the breast. Mod Pathol 3: 449, 1990

    Google Scholar 

  36. Allred DC, Clark GMR, Tandon AK, Schmitt SJ, Gilchrist KW, Osborne CK, Tormey DC, McGuire WL: Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Hum Pathol 23: 474–479, 1992

    Google Scholar 

  37. Wright C, Nicholson S, Angus B, Sainsbury JRC, Farndon J, Cairns J, Harris AL, Horne CHW: Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer 65: 118–121, 1992

    Google Scholar 

  38. Nicholson RI, McClelland RA, Finlay P, Eaton CL, Gullick WJ, Dixon AR, Robertson JFR, Ellis IO, Blamey RW: Relationship between EGF-R, c-erbB-2 protein expression and Ki67 immunostaining in breast cancer and hormone sensitivity. Eur J Cancer 29A: 1018–1023, 1993

    Google Scholar 

  39. Klijn JGM, Berns EMMJ, Foekens JA: Prognostic factors and response to therapy in breast cancer. Cancer Surv 18: 165–198, 1993

    Google Scholar 

  40. Fantl V, Richards MA, Smith R, Lammie GJA, Johnstone G, Allen D, Gregory W, Peters G, Dickson C, Barnes DM: Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer. Eur J Cancer 26: 423–429, 1990

    Google Scholar 

  41. Borg A, Sigurdsson H, Clark G, Femo M, Fuqua SAW, Olsson H, Killander D, McGuire WL: Association of INT2/HST1 coamplification in primary breast cancer with hormone-dependent phenotype and poor prognosis. Br J Cancer 63: 136–142, 1991

    Google Scholar 

  42. Henry JA, Hennessy C, Levett DL, Lennard TWJ, Westley BR, May FEB: Int 2 amplification in breast cancer: association with decreased survival and relationship to amplification of c-erbB-2 and c-myc. Int J Cancer 53: 774–780, 1993

    Google Scholar 

  43. Xiong Y, Menninger J, Beach D, Ward DC: Molecular cloning and chromosomal mapping of CCND genes encoding human D-type cyclins. Genomics 13: 575–584, 1992

    Google Scholar 

  44. Scherr CJ: G1 phase progression: cycling on cue. Cell 79: 551–555, 1994

    Google Scholar 

  45. Buckley MF, Sweeney KJE, Hamilton JA, Sini RL, Manning DL, Nicholson RI, de Fazio A, Watts CKW, Musgrove EA, Sutherland RL: Expression and amplification of cyclin genes in human breast cancer. Oncogene 8: 2127–2133, 1993

    Google Scholar 

  46. Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J: Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57: 353–361, 1994

    Google Scholar 

  47. Gillet C, Fantl V, Smith R, Fisher C, Bartek J, Dickson C, Barnes DM, Peters G: Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. Cancer Res 54: 1812–1817, 1994

    Google Scholar 

  48. McIntosh GG, Anderson H, Milton I, Steward M, Part AH, Thomas MD, Henry JA, Angus B, Lennard TWJ, Horne CHW: Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene 11: 885–891, 1995

    Google Scholar 

  49. Gillet C, Smith P, Gregory W, Richard M, Millis R, Peters G, Barnes D: Cyclin D1 and prognosis in human breast cancer. Int J Cancer 69: 92–99, 1996

    Google Scholar 

  50. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport IM, Albert DM, Dryja TP: A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643–646, 1986

    Google Scholar 

  51. Chellappan SP, Hierbert S, Mudryj M, Horowitz JM, Nevins JR: The E2F transcription factor is a cellular target for the RB protein. Cell 65: 1053–1061, 1991

    Google Scholar 

  52. Lundberg C, Skoog L, Cavanee WK, Nordenskjold M: Loss of heterozygosity in human ductal breast tumors indicates a recessive mutation on chromosome 13. Proc Natl Acad Sci USA 84: 2372–2376, 1987

    Google Scholar 

  53. T'Ang A, Varley JM, Chakraborty S, Murphree AL, Fung Y-KT: Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science 242: 263–266, 1988

    Google Scholar 

  54. Varley JM, Armour J, Swallow JE, Jeffreys AJ, Ponder BAJ, Tang A, Fung Y-KT, Brammar WJ, Walker RA: The retinoblastoma gene is frequently altered leading to loss of expression in primary breast tumours. Oncogene 4: 725–730, 1989

    Google Scholar 

  55. Borg A, Zhang Q-X, Alm P, Olsson H, Sellberg G: The retinoblastoma gene in breast cancer: allele loss is not correlated with loss of gene protein expression. Cancer Res 52: 2991–2994, 1992

    Google Scholar 

  56. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas and other neoplasms. Science 250: 1233–1238, 1990

    Google Scholar 

  57. Santibancz-Koref MF, Birch JM, Hartley AL, Norris Jones PH, Craft AH, Eden T, Crowther D, Kelsey AM, Harris M: p53 germline mutations in Li Fraumeni syndrome. Lancet 338: 1490–1491, 1991

    Google Scholar 

  58. Sidransky D, Tokins T, Helzisouer K, Rauch G, Zehnbauer B, Shelton B, Prestiglacomo L, Vogelstein B, Davidson N: Inherited p53 gene mutations in breast cancer. Cancer Res 52: 2984–2986, 1992

    Google Scholar 

  59. Warren W, Eeles RA, Ponder BAJ, Easton DF, Averill D, Ponder MA, Anderson K, Evans AM, De Mars R, Love R: No evidence for germline mutations in exons 5–9 of the p53 gene in 25 breast cancer families. Oncogene 7: 1043–1046, 1992

    Google Scholar 

  60. Varley JM, Brammar WJ, Lane DP, Swallow JE, Dolan C, Walker RA: Loss of chromosome 17p13 sequences and mutation of p53 in human breast carcinomas. Oncogene 6: 413–421, 1991

    Google Scholar 

  61. Osborne RJ, Merlo GR, Mitsudomi T, Venesio T, Liscia DS, Cappa APM, Chiba I, Takahashi T, Nau MM, Callahan R, Minna JD: Mutations in the p53 gene in primary human breast cancers. Cancer Res 51: 6194–6198, 1991

    Google Scholar 

  62. Mazars R, Spinardi L, Ben Cheikh M, Simony-Lafontaine J, Jeanteur P, Theillet C: p53 mutations occur in aggressive breast cancer. Cancer Res 52: 3918–39213, 1992

    Google Scholar 

  63. Coles C, Condie A, Chetty U, Steel CM, Evans HJ, Prosser J: p53 mutations in breast cancer. Cancer Res 52: 5291–5298, 1992

    Google Scholar 

  64. Merlo GR, Bernardi A, Diella F, Venesio T, Cappa APM, Callahan R, Liscia DS: In primary human breast carcinomas mutations in exons 5 and 6 on the p53 gene are associated with high S-phase index. Int J Cancer 53: 531–535, 1993

    Google Scholar 

  65. Andersen TI, Holm R, Nesland JM, Heimdel KR, Ottestad L, Borresen AL: Prognostic significance of TP53 alterations in breast carcinoma. Br J Cancer 68: 540–548, 1993

    Google Scholar 

  66. Caleffi M, Teague MW, Jensen RA, Vzencak-Jones CL, Dupont WD, Parl FF: p53 gene mutations and steroid receptor status in breast cancer. Cancer 73: 1247–1256, 1994

    Google Scholar 

  67. Eyfjord JE, Thorlacius S, Steinarsdottir M, Valgardsdottir R, Ogmundsdottir HM, Anamthawat-Jonsson K: p53 abnormalities and genomic instability in primary human breast carcinomas. Cancer Res 55: 646–651, 1995

    Google Scholar 

  68. Bergh J, Norbert T, Sjogren S, Lindgren A, Holmberg L: Complete sequencing of the p53 gene provides prognostic information in breast cancer patients, particularly in relation to adjuvant systemic therapy and radiotherapy. Nature Med 1: 1029–1034, 1995

    Google Scholar 

  69. Hall PA, McKee PH, Menage H, Du P, Dover R, Lane DP: High levels of p53 protein in UV-irradiated normal human skin. Oncogene 8: 203–207, 1993

    Google Scholar 

  70. Jacquemier J, Moles JP, Penault-Llorca F, Adelaide J, Torrente M, Viens P, Birnbaum D, Theillet C: p53 immunohistochemical analysis in breast cancer with four monoclonal antibodies: comparison of staining and PCR: SSCP results. Br J Cancer 69: 846–852, 1994

    Google Scholar 

  71. Fisher CJ, Gillett CE, Vojtesek B, Barnes DM, Millis R: Problems with p53 immunohistochemical staining: the effect of fixation and variation in the methods of evaluation. Br J Cancer 69: 26–31, 1994

    Google Scholar 

  72. Thor AD, Moore IDH, Edgerton SM, Kawasski ES, Reihsaus E, Lynch HT, Marcus JN, Schwartz L, Chen L-C, Mayall BH, Smith HS: Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 84: 845–855, 1992

    Google Scholar 

  73. Walker RA, Dearing SJ, Lane DP, Varley JM: Expression of p53 protein in infiltrating and in-situ breast carcinomas. J Pathol 165: 203–211, 1991

    Google Scholar 

  74. Poller DN, Hutchings CE, Galca M, Bell JA, Nicholson RA, Elston CW, Blamcy RW, Ellis IO: p53 protein expression in breast cancer carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor. Br J Cancer 66: 583–588, 1992

    Google Scholar 

  75. Barnes DM, Dublin EH, Fisher CJ, Levison DA, Millis RR: Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Human Pathol 24: 469–476, 1993

    Google Scholar 

  76. Lipponen P, Ji H, Aaltomaa S, Syrjanen S, Syrjanen K: P53 protein expression in breast cancer as related to histopathological characteristics and prognosis. Int J Cancer 55: 51–56, 1993

    Google Scholar 

  77. Sjogren S, Inganas M, Norberg T, Lindgren A, Nordgren H, Holmbergh L, Bergh J: The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 88: 173–182, 1996

    Google Scholar 

  78. Lowe SW, Rulev HE, Jacks T, Housman DE: p53 dependent apoptosis modulates the cytotoxicity of anti cancer agents. Cell 84: 957–967, 1993

    Google Scholar 

  79. Devilee P, Cornelisse CJ: Somatic genetic changes in human breast cancer. Biochem Biophys Acta 1198: 113–130, 1994

    Google Scholar 

  80. Stratton MR, Collins N, Lakhani SR, Sloane JP: Loss of hoterozygosity in ductal carcinoma in situ of the breast. J Pathol 175: 195–202, 1995

    Google Scholar 

  81. Thibodeau SN, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 269: 816–819, 1993

    Google Scholar 

  82. Wooster R, Cleton-Jansen A-M, Collins N, Mangion J, Cornelis RS, Cooper CS, Gusterson BA, Ponder BAJ, von Deimhing A, Wiestler OD, Cornelisse CJ, Devilee P, Stratton MR: Instability of short tandem repeats (microsatellites) in human cancers. Nature Genetics 6: 152–156, 1994

    Google Scholar 

  83. Yee CJ, Roodi N, Verrier CS, Parl FP: Microsatellite instability and loss of heterozygosity in breast cancer. Cancer Res 54: 1641–1644, 1994

    Google Scholar 

  84. Patel U, Grundfest-Broniatowski S, Gupta M, Banerjee S: Microsatellite instabilities in 5 chromsomes in primary breast tumours. Oncogene 9: 3695–3700, 1994

    Google Scholar 

  85. Shaw JA, Walsh T, Chappell SA, Carey N, Johnson K, Walker RA: Microsatellite instability in early breast cancer. Br J Cancer 73: 1393–1397, 1996

    Google Scholar 

  86. Miki Y, Swensen J, Shattuck-Eidens JD, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthall J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Hangen-Strauo A, Kalchen H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Norris FH, Helvering L, Morrison P, Rostek P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71, 1996

    Google Scholar 

  87. Wooster R, Bignell G, Lancaster I, Swift S, Seal S, Mangion J, Collinss N, Gregory S, Gumbs C, Micklem G, Barfoot R, Hamoudi R, Pantel S, Rice C, Biggs P, Hashim Y, Smith A, Connor F, Arason A, Gudmundsson J, Ficenec D, Kelsell D, Ford D, Tonin P, Bishop DT, Spurr NK, Ponder BAJ, Eeles R, Peto J, Devilee P, Cornelisse C, Lynch H, Narod S, Lenoir G, Egilsson V, Barkadottir RB, Lynch H, Easton DF, Bentley DR, Futreal PA, Ashworth A, Stratton MR: Identification of the breast cancer gene BRCA2. Nature 378: 789–792, 1995

    Google Scholar 

  88. Hogervorst FBL, Cornelis RS, Bout M, Van Vliet M, Oosterwijk JC, Olmer R, Bakker B, Klijn TGM, Vasen HFA, Meijers-Heijbuer H, Menko FH, Cornelisse CJ, Den Dunnen JT, Devilee P, Van Ommen G-JB: Rapid detection of BRCA1 mutations by the protein truncation test. Nature Gen 10: 208–212, 1995

    Google Scholar 

  89. Beckmann MW, Picard F, Anlt X, Van Roeyen CRC, Dominik SI, Mosny DS, Schnurch HG, Bender HG, Niederacher D: Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer 73: 1200–1226, 1996

    Google Scholar 

  90. Hosking L, Trowsdale J, Nicolai H, Solomon E, Foulkes W, Stamp G, Signer E, Jeffreys A: A somatic BRCA1 mutation in an ovarian tumour. Nature Genet 9: 343–344, 1995

    Google Scholar 

  91. Rose C, Thorpe SM, Andersen KW on behalf of Danish Breast Cancer Co-operative Group: Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet i: 16–20, 1985

    Google Scholar 

  92. King WJ, Al Sombre ER, Jensen EV, Greene GL: Comparison of immunocytochemical and steroid-binding assays for oestrogen receptor in human breast tumors. Cancer Res 45: 293–304, 1985

    Google Scholar 

  93. Andersen J, Orntoft TF, Poulsen HS: Immunohistochemical demonstration of estrogen receptor (ER) in formalin-fixed, paraffin embedded human breast cancer tissue by use of monoclonal antibody to ER. J Histochem Cytochem 36: 1553–1560, 1988

    Google Scholar 

  94. Saccani Jotti G, Johnstone SRD, Salter J, Detre S, Dowsett M: Comparison of new immunohistochemical assay for oestrogen receptor in paraffin wax embedded breast carcinoma tissue with quantitative enzyme immunoassay. J Clin Pathol 47: 900–905, 1994

    Google Scholar 

  95. McClelland RA, Wilson D, Leake R, Finlay P, Nicholson RI: A multicentre study into the reliability of steroid receptor immunocytochemical assay quantification. Eur J Cancer 27: 711–715, 1991

    Google Scholar 

  96. Barnes DM, Millis RR: Oestrogen receptors: the history, the relevance and the methods of evaluation: In: Kirkham N, Lemoine NR (eds) Progress in Pathology, Vol 2. Churchill Livingstone, Edinburgh, 1995, pp 89–114

    Google Scholar 

  97. Walter P, Green S, Greene G, Krust A, Bornert J-M, Jeltsch J-M, Staubs A, Jensen E, Serace G, Waterfield M, Chambon P: Cloning of the human oestrogen receptor. cDNA. Proc Natl Acad Sci USA 82: 7889–7893, 1985

    Google Scholar 

  98. Kumar V, Green S, Stack G, Berry M, Jin J-R, Chambon P: Functional domains of the human oestrogen receptor. Cell 51: 941–951, 1987

    Google Scholar 

  99. Umesono K, Evans RM: Determinates of target gene specificity for steroid/thyroid hormone receptors. Cell 57: 1139–1146, 1989

    Google Scholar 

  100. Koh EH, Ro J, Wildsick DM, Hortobagyi GN, Buck GN: Analysis of the oestrogen receptor gene structure of human breast cancer. Anti Cancer Res 9: 1841–1846, 1989

    Google Scholar 

  101. Watts CKW, Handel ML, King RJB, Sutherland RL: Oestrogen receptor gene structure and function in breast cancer. J Steroid Biochem Molec Biol 41: 529–536, 1992

    Google Scholar 

  102. Hill SM, Fuqua SAW, Chamness GC, Greene GL, McGuire WL: Estrogen receptor expression in human breast cancer associated with an estrogen receptor gene restriction fragment length polymorphism. Cancer Res 49: 145–148, 1989

    Google Scholar 

  103. Yaich L, Dupont WD, Cavener DR, Parl FF: Analysis of the PVU II restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res 52: 77–83, 1992

    Google Scholar 

  104. Andersen TI, Heimdel KR, Skrede M, Tyeit K, Berg K, Borresen A-L: Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility. Hum Genet 94: 665–670, 1994

    Google Scholar 

  105. Piva R, Rimondi AP, Hanan S, Moestu I, Alvisi A, Kumar VL, del Senno L: Different methylation of oestrogen receptor DNA in human breast carcinomas with and without oestrogen receptor. Br J Cancer 61: 270–275, 1990

    Google Scholar 

  106. Lapidus RG, Fergusson AT, Ottaviano YL, Parl FF, Smith HS, Weitzman SA, Baylin SA, Issa J-PJ, Davidson NE: Methylation of oestrogen and progesterone receptor gene 5 CpG islands correlates with lack of oestrogen and progesterone receptor gene expression in breast tumors. Clin Cancer Res 2: 805–810, 1996

    Google Scholar 

  107. Ottaviano YL, Issa J-P, Parl FF, Smith HS, Baylin SB, Davidson NE: Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54: 2552–2555, 1994

    Google Scholar 

  108. Fergusson AT, Lapidus RG, Baylin SB, Davidson NE: Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res 55: 2279–2283, 1995

    Google Scholar 

  109. Sluyser M: Steroid/thyroid receptor-like proteins with oncogenic potential: a review. Cancer Res 50: 451–458, 1990

    Google Scholar 

  110. Garcia T, Lehrer S, Bloomer WD, Schachter B: A variant estrogen receptor messenger ribonucleic acid is associated with reduced levels of estrogen binding in human mammary tumors. Mol Endocrinol 2: 785–791, 1988

    Google Scholar 

  111. Schmutzler RK, Sanchez M, Lehrer S, Chaparro C, Phillips C, Rabin J, Schachter B: Incidence of estrogen receptor polymorphism in breast cancer patients. Breast Cancer Res Treat 19: 111–117, 1991

    Google Scholar 

  112. Scott GK, Kushner P, Vigne J-L, Benz CC: Truncated forms of DNA-binding estrogen receptors in human breast cancer. J Clin Invest 88: 700–706, 1991

    Google Scholar 

  113. Fuqua SAW, Allred DC, Elledge RM, Kreig SL, Benedix MG, Nawaz Z, O'Malley BW, Greene GL, McGuire WL: The ER-positive/PgR negative breast cancer phenotype is not associated with mutations within the DNA binding domain. Breast Cancer Res Treat 26: 191–202, 1993

    Google Scholar 

  114. Murphy LC, Dotzlaw H: Variant estrogen receptor mRNA species detected in human breast cancer biopsy samples. Mol Endocrinol 3: 687–693, 1989

    Google Scholar 

  115. Dotzlaw H, Ackhalaf M, Murphy LC: Characterization of estrogen receptor variant in mRNAs from human breast cancers. Mol Endocrinol 3: 687–693, 1989

    Google Scholar 

  116. Murphy LC, Hilsenbeck SG, Dotzlaw H, Fuqua SAW: Relationship of clone 4 estrogen receptor variant messenger RNA expression to know prognostic variables in human breast cancer. Clin Cancer Res 1: 155–159, 1995

    Google Scholar 

  117. Fuqua SAW, Falette NF, McGuire WL: Sensitive detection of estrogen receptor mRNA by polymerase chain reaction assay. J Natl Cancer Inst 82: 858–861, 1990

    Google Scholar 

  118. Fuqua SAW, Fitzgerald SD, Chamness GC, Tandon AK, McDonnell DP, Nawaz Z, O'Malley BW, McGuire WL: Variant human breast tumor estrogen receptor with constitutive transcriptional activity. Cancer Res 51: 105–109, 1991

    Google Scholar 

  119. Fuqua SAW, Fitzgerald SD, Allred DC, Elledge RM, Nawaz Z, McDonnell DP, O'Maley BW, Greene GL, McGuire WL: Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res 52: 483–486, 1992

    Google Scholar 

  120. Karwik PS, Kulkarni S, Liu X-P, Budd GT, Bukowski RM: Estrogen receptor mutations in tamoxifen-resistant breast cancer. Cancer Res 54: 349–353, 1994

    Google Scholar 

  121. Daffala AAI, Johnston SRD, Smith IE, Detre S, King N, Dowsett M: Exon 5 deletion variant estrogen receptor messenger RNA expression in relation to tamoxifen resistance and progesterone receptor/pS2 status in human breast cancer. Cancer Res 55: 288–293, 1995

    Google Scholar 

  122. Roodi N, Bailey LR, Yuo N-Y, Verrier CS, Yee CJ, Dupont LD, Parl FF: Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J Natl Cancer Inst 87: 446–451, 1995

    Google Scholar 

  123. Rajakariar R, Walker RA: Pathological and biological features of mammographically detected invasive breast carcinomas. Br J Cancer 71: 150–154, 1995

    Google Scholar 

  124. Fuqua SAW, Hill SM, Chamness GC, Benedix MG, Green GL, O'Malley BW, McGuire WL: Progesterone receptor gene restriction fragment length polymorphisms in human breast tumours. J Natl Cancer Inst 83: 1157–1160, 1991

    Google Scholar 

  125. Walker RA, Varley JM: The molecular pathology of human breast cancer. Cancer Surv 16: 31–57, 1993

    Google Scholar 

  126. Masiakowski P, Breathnach R, Bloch J, Gannon T, Krust A, Chambon P: Cloning of cDNA sequences of hormone regulated genes from the MCF-7 human breast cancer cell line. EMBO J 10: 7895–7903, 1982

    Google Scholar 

  127. May FEB, Westley BR: Cloning of estrogen-regulated messenger RNA sequences from human breast cancer cells. Cancer Res 46: 603–6040, 1986

    Google Scholar 

  128. Skilton RA, Luqmani YA, McClelland RA, Coombs RC: Characterisation of a messenger RNA selectively expressed in human breast cancer. Br J Cancer 60: 168–175, 1989

    Google Scholar 

  129. Henry JA, Nicholson S, Hennessy C, Lenard TWJ, May FEB, Westley BR: Expression of oestrogen regulated pNR −2 mRNA in human breast cancer: relation to oestrogen receptor mRNA levels and response to endocrine therapy. Br J Cancer 50: 3832–3837, 1989

    Google Scholar 

  130. Koerner FC, Goldberg D, Edgerton SM, Schwartz LH: pS2 protein and steroid hormone receptors in invasive breast carcinomas. Int J Cancer 52: 183–188, 1992

    Google Scholar 

  131. Walker RA, Rajakariar R, Dookeran KA: Comparison of pS2 and cathepsin D in primary breast carcinoma. The Breast 4: 137–142, 1995

    Google Scholar 

  132. Henry JA, Piggott NH, Mallick VK, Nicholson S, Farndon JR, Westley BR, May FEB: pNR-2/pS2 immunohistochemical staining in breast cancer: correlation with prognostic factors and endocrine response. Br J Cancer 62: 615–622, 1991

    Google Scholar 

  133. Carr M, May FEB, Lennard TWJ, Westley BR: Determination of oestrogen responsiveness of breast cancer by competitive reverse transcription-polymerase chain reaction. Br J Cancer 72: 1427–1434, 1995

    Google Scholar 

  134. Poulson R, Wright NA: Trefoil peptides: a newly recognised family of epithelial mucin-associated molecules. Am J Physiol 265: 205–213, 1993

    Google Scholar 

  135. Nunez A-M, Berry M, Imler J-L, Chambon P: The 5′ flanking region of the pS2 gene contains a complex enhancer region responsive to oestrogens, epidermal growth factor, a tumour promoter (TPA), the c-H-ras oncoprotein and the c-jun protein. EMBO J 8: 823–829, 1989

    Google Scholar 

  136. Dookeran KA, Rye PD, Dearing SJ, Walker RA: Expression of the pS2 peptide in primary breast carcinomas: comparison of membrane and cytoplasmic staining patterns. J Pathol 171: 123–129, 1993

    Google Scholar 

  137. Westley BR, Rochefort H: A secreted glycoprotein induced by oestrogen in human breast cancer cell lines. Cell 20: 353–362, 1980

    Google Scholar 

  138. Thorpe SM, Rochefort H, Garcia M, Freiss G, Christensen J, Khalaf S, Paoluccii F, Parr B, Rasmussen BB, Rose C: Association between high concentrations of 52 k cathepsin D and poor prognosis in primary breast cancer. Cancer Res 49: 6008–6014, 1989

    Google Scholar 

  139. Tandon AC, Clarke GM, Chamness GC, Chirgwin JM, McGuire WL: Cathepsin D and prognosis in breast cancer. N Engl J Med 322: 297–302, 1990

    Google Scholar 

  140. Duffy MJ, Brouillet J P, Reilly D, McDermott E, O'Higgins N, Fennelly J, Maudelonde T, Rochefort H: Cathepsin D concentration in breast cancer eytosols: correlation with biochemical, histological and clinical findings. Clin Chem 37: 101–104, 1991

    Google Scholar 

  141. Garcia M, Derocq P, Pujol P, Rochefort H: Overexpression of transfected cathepsin D in transformed cells increased their malignant phenotype and metastatic potency. Oncogene 5: 1809–1814, 1990

    Google Scholar 

  142. Walker RA, Denley H, Dookeran KA: Cathepsin D in breast carcinomas—the role of the stromal cell component. Oncology Rep 1: 227–231, 1994

    Google Scholar 

  143. Thor A, Benz C, Moore D, Goldman E, Edgerton S, Landry J, Schwartz L, Mayall B, Hickey E, Weber LA: Stress response protein (srp-27) determination in primary human breast carcinomas: Clinical histologic and prognostic correlations. J Natl Cancer Inst 83: 170–178, 1991

    Google Scholar 

  144. Manning DL, Robertson JFR, Ellis IO, Elston CW, McClelland RA, Gee JMW, Jones RJ, Green CD, Cannon P, Blamey RW, Nicholson RI: Oestrogen regulated genes in breast cancer: association of pLIV1 with lymph node involvement. Eur J Cancer 30A: 675–678, 1994

    Google Scholar 

  145. Downward J, Yarden Y, Mayes E, Scarce G, Totty N, Stockwell P, Ullrich A, Schlessinger J, Waterfield MD: Close similarity of epidermal growth factor receptor and v-erbB oncogene protein sequences. Nature 307: 521–527, 1984

    Google Scholar 

  146. Sainsbury JRC, Needham GC, Malcolm A, Farndon JR, Harris AL: Epidermal growth factor receptor status as predictor of recurrence and of death from breast cancer. Lancet 1: 1398–1402, 1987

    Google Scholar 

  147. Klijn JGM, Berns PMJJ, Schmitz PIM, Foekens JA: The clinical significance of epidermal growth factor receptor in breast cancer: a review of 5232 patients. Endocr Rev 13: 3–17, 1992

    Google Scholar 

  148. Nicholson S, Halcrow P, Farndon JR, Sainsbury JRC, Chambers P, Harris AL: Expression of epidermal growth factor receptors associated with lack of response to endocrine therapy in recurrent breast cancer. Lancet i: 182–185, 1989

    Google Scholar 

  149. Nicholson RI, McClelland RA, Gee JMW, Manning DL, Cannon P, Robertson JFR, Ellis IO, Blamey RW: Epidermal growth factor recexpression in breast cancer: association with response to endocrine therapy. Br Cancer Res Treat 29: 117–125, 1994

    Google Scholar 

  150. Harris AL, Nicholson S: Epidermal growth factor receptors in human breast cancer. Cancer Treat Res 40: 93–118, 1988

    Google Scholar 

  151. Chrysogelos SA, Yarden RI, Lauber AH, Murphy JM: Mechanisms of EGF receptor regulation in breast cancer cells. Br Cancer Res Treat 31: 227–236, 1994

    Google Scholar 

  152. Roberts AB, Thompson NL, Heine V, Flanders K, Sporn MB: Transforming growth factor beta1: possible roles in carcinogenesis. Br J Cancer 57: 594–600, 1988

    Google Scholar 

  153. Knabbe C, Lippman ME, Wakefield LM, Flanders KC, Kasid AL, Derynck R, Dickson RB: Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48: 417–428, 1987

    Google Scholar 

  154. Arrick BA, Lopez AR, Elfman F, Ebner R, Damsky CH, Derynck R: Altered metabolic and adhesive properties and increased tumorigenicity associated with increased expression of transforming growth factor β1. J Cell Biol 118: 715–726, 1992

    Google Scholar 

  155. Dutta A, MacLennan K, Flanders KC, Sacks NPM, Smith I, McKinna A, Dowsett M, Wakefield LM, Sporn MB, Baum M, Colletta AA: Induction of transforming growth factor β1 in human breast cancer in vivo following tamoxifen treatment. Cancer Res 52: 4261–4264, 1992

    Google Scholar 

  156. Benson JR, Wakefield LM, Baum M, Colletta AA: Synthesis and secretion of transforming growth factor beta isoforms by primary cultures of human breast tumour fibroblasts in vitro and their modulation by tamoxifen. Br J Cancer 74: 352–358, 1996

    Google Scholar 

  157. MacCallum J, Keen JC, Bartlett JMS, Thompson AM, Dixon JM, Miller WR: Changes in expression of transforming growth factor beta mRNA isoforms in patients undergoing tamoxifen therapy. Br J Cancer 74: 474–478, 1996

    Google Scholar 

  158. Walker RA, Dearing SJ: Transforming growth factor beta1 in ductal carcinoma in-situ and invasive carcinomas of the breast. Eur J Cancer 28: 641–644, 1992

    Google Scholar 

  159. Gorsch SM, Moli VA, Stukel TA, Gold LJ, Arrick BA. Immunohistochemical staining for transforming growth factor β1 associates with disease progression in human breast cancer. Cancer Res 52: 6949–6952, 1992

    Google Scholar 

  160. Dalal BI, Keown PA, Greenberg H: Immunocytochemical localization of secreted transforming growth factor β1 to the advancing edges of primary tumours and to lymph node metastases of human mammary carcinoma. Am J Pathol 143: 381–389, 1993

    Google Scholar 

  161. Walker RA, Dearing SJ, Gallacher B: Relationship of transforming growth factor beta1 to extracellular matrix and stromal infiltrates in invasive breast carcinoma. Br J Cancer 69: 1160–1165, 1994

    Google Scholar 

  162. Walker RA, Gallacher B: Determination of transforming growth factor beta1 mRNA expression in breast carcinomas by in situ hybridization. J Pathol 177: 123–127, 1995

    Google Scholar 

  163. Kemler R: Classical cadherins. Semin Cell Biol 3: 149–155, 1992

    Google Scholar 

  164. Kembler R: From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet 9: 317–321, 1993

    Google Scholar 

  165. Vleminckx K, Vakaet L, Mareel MM, Fiers W, Van Roy F: Genetic manipulation of E-cadherin expression by epithelial tumour cells reveals an invasion suppressor role. Cell 66: 107–119, 1991

    Google Scholar 

  166. Moll R, Mitze M, Frixen VH, Birchmeier W: Differential loss of E-cadherin in infiltrating ductal and lobular breast carcinomas. Am J Pathol 143: 1731–1742, 1993

    Google Scholar 

  167. Oka H, Shiozaki H, Kobayashi K, Inove M, Tahara H, Kobayashi T, Takatsuka Y, Matsuyoshi N, Hirno S, Takeichi M, Mori T: Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res 53: 1696–1701, 1993

    Google Scholar 

  168. Lipponen P, Saarelainen E, Ji H, Aaltomaa S, Syrjanen K: Expression of E-cadherin (E-Cd) as related to other prognostic factors and survival in breast cancer. J Pathol 174: 101–109, 1994

    Google Scholar 

  169. Jones JL, Royall JE, Walker RA: E-cadherin relates to EGFR expression and lymph node metastasis in primary breast carcinoma. Br J Cancer 74: 1237–1241, 1996

    Google Scholar 

  170. Lindblom A, Rotstein S, Skoog L, Nordenskjold M, Larsson C: Deletions on chromosome 16 primary breast carcinomas are associated with development of distant metastases. Cancer Res 53: 3707–3711, 1993

    Google Scholar 

  171. Rasbridge SA, Gillett CE, Sampson SA, Walsh FS, Millis RR: Epithelial (E-) and placental (P-) cadherin cell adhesion molecule expression in breast carcinoma. J Pathol 169: 245–250, 1993

    Google Scholar 

  172. Kanai Y, Oda T, Tsuda H, Ochiai A, Hirohashi S: Point mutation of the E-cadherin gene in invasive lobular carcinoma of the breast. Jpn J Cancer Res 85: 1035–1039, 1994

    Google Scholar 

  173. Berx G, Cleton-Jansen A-M, Nollet F, De Leeuw JF, Van der Vijver MJ, Cornelisse C, Van Roy F: E-cadherin in a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 14: 6107–6115, 1995

    Google Scholar 

  174. Kashiwaba M, Tamura G, Suzuki Y, Maesawa C, Ogasawara S, Sakata K, Sotadate R: Epithelial cadherin gene is not mutated in ductal carcinomas of the breast. Jpn J Cancer Res 86: 1054–1059, 1995

    Google Scholar 

  175. Hynes RO: Integrins, versatility, modulation and signalling in cell adhesion. Cell 69: 11–25, 1992

    Google Scholar 

  176. Zutter MM, Krigman HR, Santoro SA: Altered integrin expression in adenocarcinoma of the breast. Analysis by in situ hybridization. Am J Pathol 142: 1439–1448, 1993

    Google Scholar 

  177. Zutter MM, Mazoujian G, Santoro SA: Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast. Am J Pathol 137: 863–870, 1990

    Google Scholar 

  178. Pignatelli M, Hanby AN, Stamp GWH: Low expression of β1, α2 and α3 subunits of VLA integrins in malignant mammary tumours. J Pathol 165: 25–32, 1994

    Google Scholar 

  179. Natali PG, Nicotra MR, Botti C, Mottolese M, Bigothi A, Segatto O: Changes in expression of α6/β4 integrin heterodimer in primary and metastatic breast cancer. Br J Cancer 66: 318–322, 1992

    Google Scholar 

  180. Jones JL, Critchley DR, Walker RA: Alteration of stromal protein and integrin expression in breast — a marker of premalignant change? J Pathol 167: 399–406, 1992

    Google Scholar 

  181. Pignatelli M, Cardillo MR, Hanby A, Stamp GWH: Integrins and their accessory adhesion molecules in mammary carcinomas: loss of polarization in poorly differentiated tumours. Hum Pathol 23: 1159–1166, 1992

    Google Scholar 

  182. Blasi F, Vassalli JD, Dano K: Urokinase-type plasminogen activate: proenzyme, receptor are inhibitors. J Cell Biol 104: 801–804, 1987

    Google Scholar 

  183. Duffy MJ, Reilly D, O'Sullivan C, O'Higgins N, Fennelly JJ, Andreasen P: Urokinase-plasminogen activator, a new and independent prognostic marker in breast cancer. Cancer Res 50: 6827–6829, 1990

    Google Scholar 

  184. Janicke F, Schmitt M, Pache L, Ulm K, Harbeck N, Hoefler H, Graeff H: Urokinase (uPA) and its inhibitor PAI-1 are strong independent prognostic factors in node negative breast cancers. Br Cancer Res Treat 24: 195–208, 1993

    Google Scholar 

  185. Grondhahl-Hansen J, Christensen IJ, Rosenquist C, Brunner N, Mouridsen HT, Dano K, Buchet-Toft M: High levels of urokinase-type plasminogen activation and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 53: 2573–2521, 1993

    Google Scholar 

  186. Bouchet C, Spyratos F, Martin PM, Hacene K, Gentile A, Oglobine J: Prognostic value of urokinase-type plasminogen activator and its inhibitor PAI-1 and PAI-2 in breast carcinomas. Br J Cancer 69: 398–405, 1994

    Google Scholar 

  187. Constantini V, Sidoni A, Deveglia R, Cazzoto OA, Bellezza G, Ferri I, Bucciarelli E, Nenci GG: Combined over-expression of urokinase, urokinase receptor, and plasminogen activator inhibitor-1 is associated with breast cancer progression. Cancer 77: 1079–1088, 1996

    Google Scholar 

  188. Pyke C, Graem N, Ralfkiaer N, Hoeyer-Hansen G, Brunner N, Dano K: Receptor for urokinase in present in tumour-associated macrophages in ductal breast carcinoma. Cancer Res 53: 1911–1915, 1993

    Google Scholar 

  189. Bianchi E, Cohen RL, Thor AT, Todd III RF, Mizukami IF, Lawrence DA, Ljung BM, Shuman MA, Smith HS: The urokinase receptor is expressed in invasive breast cancer but not in normal breast tissue. Cancer Res 54: 841–866, 1994

    Google Scholar 

  190. Woessner JF: Matrix metalloproteinases and their inhibitors in connective tissue remodelling. FASEB J 5: 2145–2154, 1991

    Google Scholar 

  191. Powell WC, Matrisian LM: Complex roles of matrix metalloproteinases in tumour progression. In: Gunthert U, Schleg PM, Birchmeier W (eds) Attempts to Understand Metastasis Formation. 1. Metastasis Related Molecules. Springer-Verlag, Heidelburg, 1996, pp 1–21

    Google Scholar 

  192. Cawston TE: Protein inhibitors of metalloproteinases. In: Barnett AJ, Salvesen G (eds) Proteinase Inhibitors. Elsevier, Amsterdam, 1986, pp 589–610

    Google Scholar 

  193. Uria JA, Ferrando AA, Velasco G, Freije JMP, Lopez-Otin C: Structure and expression in breast tumours of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res 54: 2091–2094, 1994

    Google Scholar 

  194. Monteagudo C, Merino MJ, San JJ, Liotta LA, Stetler-Stevenson WG: Immunohistochemical distribution of type IV collogenase in normal, benign and malignant breast tissue. Am J Pathol 136: 585–592, 1990

    Google Scholar 

  195. Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR: Activity of type IV collagenases in benign and malignant breast disease. Br J Cancer 67: 1126–1131, 1993

    Google Scholar 

  196. D'Errieo A, Gerbisa S, Liotta LA, Castronovo V, Stetler-Stevenson WG, Grigioni WF: Augmentation of type IV collagenase, laminin receptor and Ki 67 proliferation antigen associated with human colon, gastric and breast carcinoma progression. Mod Pathol 4: 239–246, 1991

    Google Scholar 

  197. Iwata H, Kobayashi S, Iwase H, Masaoka A, Fujimoto N, Okada Y: Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. Jpn J Cancer Res 87: 602–611, 1996

    Google Scholar 

  198. Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC, Chambon P: A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 348: 699–704, 1990

    Google Scholar 

  199. Kawami H, Yoshida K, Ohsaki A, Kuroi K, Nishiyama M, Toge T: Stromelysin-2 mRNA expression and malignancy: comparison with clinicopathological features and type IV collagenase mRNA expression in breast tumors. Anticancer Res 13: 2319–2324, 1993

    Google Scholar 

  200. Hahnel E, Harvey JM, Joyce R, Robbins RD, Sterrett GF, Hahnel R: Stromelysin-3 expression in breast cancer biopsies: clinicopathological correlations. Int J Cancer 55: 771–774, 1993

    Google Scholar 

  201. Engel G, Heseemeyer K, Auer G, Backdahl M, Eriksson E, Linder S: Correlation between stromelysin-3 level and outcome of human breast cancer. Int J Cancer 58: 1–7, 1994

    Google Scholar 

  202. Onisto M, Riccio MP, Scannapieco P, Caenozzo C, Griggio L, Spina M, Stetler-Stevenson WG, Garibsa S: Gelatinase A/TIMP-2 imbalance in lymph node positive breast cancer as measured by RT-PCR. Int J Cancer 63: 621–626, 1995

    Google Scholar 

  203. Kossakowska AG, Huchcroft SA, Urbanski SJ, Edwards DR: Comparative analysis or the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin's lymphomas in humans. Br J Cancer 73: 1401–1408, 1996

    Google Scholar 

  204. Poulsom R, Hanby AM, Pignatelli M, Jeffrey RE, Longcroft JM, Rogers L, Stamp GWH: Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic libroblasts in both mammary carcinomas and basal carcinomas of the skin. J Clin Pathol 46: 429–436, 1993

    Google Scholar 

  205. Soini Y, Hurskaincn T, Hoyhtya M, Oikarincn A, Autio-Harmainen H: 72 kD and 92 kD type collagenase, type IV collagen and laminin mRNAs in breast cancer: a study by in situ hybridisation. J Histochem Cytochem 42: 945–951, 1994

    Google Scholar 

  206. Emonard H, Remack A, Boel A, Grimaud JA, Stetler-Stevenson WG, Foidart JM: Tumour cell surface associated binding site for the Mr 72,000 type IV collagenase. Cancer Res 52: 5845–5848, 1992

    Google Scholar 

  207. Sato H, Takino T, Okado Y, Cao J, Shinagawa A, Yamamoto E, Seiki M: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370: 61–65, 1994

    Google Scholar 

  208. Will H, Hinzmann B: cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment. Eur J Biochem 231: 602–608, 1995

    Google Scholar 

  209. Sato H, Seiki M: Membrane-type matrix metalloproteinases (MT-MMPs) in tumour metastasis. J Biochem 119: 209–215, 1996

    Google Scholar 

  210. Takino T, Sato H, Shinagawa A, Seiki M. Identification of the second membrane type matrix metalloproteinase (MT-MMP2) gene from a human placenta cDNA library: MT-MMP form a unique membrane-type subclass in the MMP family. J Biol Chem 270: 23013–23020, 1995

    Google Scholar 

  211. Nomura H, Sato H, Seiki M, Mai M, Okada Y: Expression of membrane-type matrix metalloproteinase in human gastric carcinomas. Cancer Res 55: 3263–3266, 1995

    Google Scholar 

  212. Tokuraku M, Sato H, Murakami S, Okoda Y, Watanabe Y, Seiki M: Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase (MT-MMP) and with lymph node metastasis. Int J Cancer 64: 355–359, 1995

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University of Leicester, Breast Cancer Research Unit, Clinical Sciences, Glenfield Hospital NHS Trust, Groby Road, Leicester, LE3 9QP, UK

    Rosemary A. Walker, J. Louise Jones, Stephen Chappell, Tom Walsh & Jacqueline A. Shaw

Authors
  1. Rosemary A. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Louise Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen Chappell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tom Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jacqueline A. Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Walker, R.A., Jones, J.L., Chappell, S. et al. Molecular pathology of breast cancer and its application to clinical management. Cancer Metastasis Rev 16, 5–27 (1997). https://doi.org/10.1023/A:1005740222307

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005740222307

Search

Navigation