Abstract
Breast cancer is the most common malignancy in women and comprises 18% of all female cancers. The incidence of breast cancer increases with age and in the western countries the disease is the single most common cause of death among women aged 40–50, accounting for about a fifth of all deaths in this age group. The advent of mammography screening has led to an increased detection of pre-invasive mammary lesions and a better elucidation of the pathological events that precede the development of invasive breast carcinoma. Invasive breast cancer is classified in two main morphological subtypes ductal carcinoma representing about 80% of breast malignancy, and lobular carcinoma that accounts for approximately 10% of breast cancers. Among pre-invasive breast lesions, the hyperplasia of the usual type (HUT) is morphologically and phenotypically heterogeneous, whereas atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are homogenous in cell type and marker expression. On the basis of epidemiological and clinical data ADH at the present is seen as a risk factor and not as a direct precursor of DCIS or invasive lesions. Thus the only proliferative lesion that can be considered as a true precursor of invasive breast cancer is DCIS. This model of pathological progression is partially corroborated by genetic studies. In recent years progresses were made in defining some of the critical processes involved in breast cancer development and progression, and CpG island hypermethylation is emerging as one of the main mechanisms for inactivation of cancer related genes in breast tumorigenesis. Three types of genes are involved in carcinogenesis: oncogenes, tumor suppressor genes (TSGs) and stability (caretaker) genes. They encode for proteins involved in a series of pathways that control the basic functions of the cell: proliferation, communication with neighboring cells and with extra cellular matrix, senescence and programmed cell death (apoptosis). Epigenetic mechanism can modulate these pathways by acting directly on tumor suppressor genes and stability genes and indirectly on oncogenes through their regulators. Studies on several tumor types indicate changes in the number of methylated genes as well as an increase in methylation density during tumor progression, but only few studies have investigated changes in promoter hypermethylation during breast cancer progression. This is mainly due to the intrinsic difficulties to collect lesions that might be representative of all stages of the diseases. An increase in promoter hypermethylation was demonstrated for CCND2, ESR1, CDH1, RASSF1A, AP2α, Twist and maspin from DCIS to invasive tumor. In distant metastases from bone, brain and lung the frequency of methylation for CCND2, RASSF1A, Twist, RARβ2 and HIN1 was statistically significant different as compared with the primary tumor. The analysis of six cases of paired primary tumors and lymph node metastasis showed same methylation patterns for all but one case. The identification of changes in methylation distribution during breast cancer progression is fundamental not only for a better comprehension of the mechanisms involved in breast carcinogenesis, but because such alterations may represent potential markers for early cancer detection and for a better definition of the prognosis.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Parkin D. M., Bray F. I. and Devesa S. S. Cancer burden in the year 2000. The global picture. Eur J Cancer, 2001;37Suppl 8: S4–66.
Rudland P. S. “Mammary stem cells in normal development and cancer.” In, Stem cells, C. S. Potten ed.: Academic Press, 1997.
Howard B. A. and Gusterson B. A. Human breast development. J Mammary Gland Biol Neoplasia, 2000;5: 119–137.
Osborne M. P. “Breast development and anatomy in Disease of the Breast”. In, Disease of the Breast, Jay R. Harris, Lippman, Marc E., Morrow, Monica, Hellman, S. ed., Philadelphia: Lippincott-Raven Publ, 1996.
Potten C. S., Watson R. J., Williams G. T., Tickle S., Roberts S. A., Harris M. and Howell A. The effect of age and menstrual cycle upon proliferative activity of the normal human breast. Br J Cancer, 1988;58: 163–170.
Smalley M. and Ashworth A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer, 2003;3: 832–44.
Kordon E. C. and Smith G. H. An entire functional mammary gland may comprise the progeny from a single cell. Development, 1998;125: 1921–1930.
Dontu G., El-Ashry D. and Wicha M. S. Breast cancer, stem/progenitor cells and the estrogen receptor. Trends Endocrinol Metab, 2004;15: 193–197.
Reya T., Morrison S. J., Clarke M. F. and Weissman I. L. Stem cells, cancer, and cancer stem cells. Nature, 2001;414: 105–111.
Pardal R., Clarke M. F. and Morrison S. J. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer, 2003; 3: 895–902.
Dontu G., Al-Hajj M., Abdallah W. M., Clarke M. F. and Wicha M. S. Stem cells in normal breast development and breast cancer. Cell Prolif, 2003; 36Suppl 1: 59–72.
Singh S. K., Clarke I. D., Terasaki M., Bonn V. E., Hawkins C., Squire J. and Dirks P. B. Identification of a cancer stem cell in human brain tumors. Cancer Res, 2003; 63: 5821–5828.
Ignatova T. N., Kukekov V. G., Laywell E. D., Suslov O. N., Vrionis F. D. and Steindler D. A. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia, 2002; 39: 193–206.
Al-Hajj M., Wicha M. S., Benito-Hernandez A., Morrison S. J. and Clarke M. F. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 2003; 100: 3983–3988.
Naylor S., Smalley M. J., Robertson D., Gusterson B. A., Edwards P. A. and Dale T. C. Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium. J Cell Sci, 2000; 113 (Pt 12): 2129–2138.
Diallo R., Schaefer K. L., Poremba C., Shivazi N., Willmann V., Buerger H., Dockhorn-Dworniczak B. and Boecker W. Monoclonality in normal epithelium and in hyperplastic and neoplastic lesions of the breast. J Pathol, 2001; 193: 27–32.
Smith G. H. Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat, 1996; 39: 21–31.
Weissman I. L., Anderson D. J. and Gage F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu Rev Cell Dev Biol, 2001; 17: 387–403.
Smith C. A., Monaghan P. and Ellis J. Epithelial cells of the normal human breast. J Pathol, 1985; 146: 221–226.
Smith C. A., Monaghan P. and Neville A. M. Basal clear cells of the normal human breast. Virchows Arch A Pathol Anat Histopathol 1984;402: 319–329.
Ferguson D. J. An ultrastructural study of mitosis and cytokinesis in normal ‘resting’ human breast. Cell Tissue Res, 1988; 252: 581–587.
Stingl J., Eaves C. J., Kuusk U. and Emerman J. T. Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. Differentiation, 1998; 63: 201–213.
Stingl J., Eaves C. J., Zandieh I. and Emerman J. T. Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Res Treat, 2001; 67: 93–109.
Gudjonsson T., Villadsen R., Nielsen H. L., Ronnov-Jessen L., Bissell M. J. and Petersen O. W. Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties. Genes Dev, 2002; 16: 693–706.
Pechoux C., Gudjonsson T., Ronnov-Jessen L., Bissell M. J. and Petersen O. W. Human mammary luminal epithelial cells contain progenitors to myoepithelial cells. Dev Biol, 1999;,206: 88–99.
Foote F. W. Lobular carcinoma in situ. A rare form of mammary cancer. Am J Pathol, 1941; 17: 491–496.
Reis-Filho J. S. and Lakhani S. R. The diagnosis and management of pre-invasive breast disease: genetic alterations in pre-invasive lesions. Breast Cancer Res, 2003; 5: 313–319.
Page D. L. and Dupont W. D. Anatomic indicators (histologic and cytologic) of increased breast cancer risk. Breast Cancer Res Treat, 1993; 28: 157–166.
Dupont W. D. and Page D. L. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med, 1985; 312: 146–151.
Fitzgibbons P. L., Henson D. E. and Hutter R. V. Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement. Cancer Committee of the College of American Pathologists. Arch Pathol Lab Med, 1998; 122: 1053–1055.
Boecker W., Buerger H., Schmitz K., Ellis I. A., van Diest P. J., Sinn H. P., Geradts J., Diallo R., Poremba C. and Herbst H. Ductal epithelial proliferations of the breast: a biological continuum? Comparative genomic hybridization and high-molecular-weight cytokeratin expression patterns. J Pathol, 2001; 195: 415–421.
Boecker W., Moll R., Dervan P., Buerger H., Poremba C., Diallo R. I., Herbst H., Schmidt A., Lerch M. M. and Buchwalow I. B. Usual ductal hyperplasia of the breast is a committed stem (progenitor) cell lesion distinct from atypical ductal hyperplasia and ductal carcinoma in situ. J Pathol, 2002; 198: 458–467.
Page D. L., Dupont W. D., Rogers L. W. and Rados M. S. Atypical hyperplastic lesions of the female breast. A long-term follow-up study. Cancer, 1985; 55: 2698–2708.
Bartow S. A., Pathak D. R., Black W. C., Key C. R. and Teaf S. R. Prevalence of benign, atypical, and malignant breast lesions in populations at different risk for breast cancer. A forensic autopsy study. Cancer, 1987; 60: 2751–2760.
Stomper P. C., Cholewinski S. P., Penetrante R. B., Harlos J. P. and Tsangaris T. N. Atypical hyperplasia: frequency and mammographic and pathologic relationships in excisional biopsies guided with mammography and clinical examination. Radiology, 1993; 189: 667–671.
Page D. L. and Jensen R. A. Evaluation and management of high risk and premalignant lesions of the breast. World J Surg, 1994; 18: 32–38.
Dupont W. D., Parl F. F., Hartmann W. H., Brinton L. A., Winfield A. C., Worrell J. A., Schuyler P. A. and Plummer W. D. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer, 1993; 71: 1258–1265.
Ma L. and Boyd N. F. Atypical hyperplasia and breast cancer risk: a critique. Cancer Causes Control, 1992; 3: 517–525.
London S. J., Connolly J. L., Schnitt S. J. and Colditz G. A. A prospective study of benign breast disease and the risk of breast cancer. Jama, 1992; 267: 941–944.
Tavassoli F. A. and Norris H. J. A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast. Cancer, 1990; 65: 518–529.
Page D. L. and Dupont W. D. Indicators of increased breast cancer risk in humans. J Cell Biochem Suppl, 1992; 16G: 175–182.
van Dongen J. A., Fentiman I. S., Harris J. R., Holland R., Peterse J. L., Salvadori B. and Stewart H. J. In-situ breast cancer: the EORTC consensus meeting. Lancet, 1989;, 2: 25–27.
Page D. L., Dupont W. D., Rogers L. W. and Landenberger M. Intraductal carcinoma of the breast: follow-up after biopsy only. Cancer, 1982; 49: 751–758.
Faverly D. R., Burgers L., Bult P. and Holland R. Three dimensional imaging of mammary ductal carcinoma in situ: clinical implications. Semin Diagn Pathol, 1994; 11: 193–198.
Holland R., Hendriks J. H., Vebeek A. L., Mravunac M. and Schuurmans Stekhoven J. H. Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet, 1990; 335: 519–522.
Lagios M. D. Duct carcinoma in situ. Pathology and treatment. Surg Clin North Am, 1990; 70: 853–871.
Page D. L., Dupont W. D., Rogers L. W., Jensen R. A. and Schuyler P. A. Continued local recurrence of carcinoma 15–25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer, 1995; 76: 1197–1200.
Betsill W. L., Jr., Rosen P. P., Lieberman P. H. and Robbins G. F. Intraductal carcinoma. Long-term follow-up after treatment by biopsy alone. Jama, 1978; 239: 1863–1867.
Ketcham A. S. and Moffat F. L. Vexed surgeons, perplexed patients, and breast cancers which may not be cancer. Cancer, 1990; 65: 387–393.
Couch F. J., Weber, B.L. “Breast Cancer”. In, The Genetic Basis of Human Cancer, Bert Vogelstein, Kinzler, Kenneth W. ed., New York: McGraw-Hill, 1998.
Haagensen C. D., Lane N., Lattes R. and Bodian C. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer, 1978; 42: 737–769.
Wheeler J. E., Enterline H. T., Roseman J. M., Tomasulo J. P., McIlvaine C. H., Fitts W. T., Jr. and Kirshenbaum J. Lobular carcinoma in situ of the breast. Long-term followup. Cancer, 1974; 34: 554–563.
Sapino A., Frigerio A., Peterse J. L., Arisio R., Coluccia C. and Bussolati G. Mammographically detected in situ lobular carcinomas of the breast. Virchows Arch, 2000; 436: 421–430.
Georgian-Smith D. and Lawton T. J. Calcifications of lobular carcinoma in situ of the breast: radiologic-pathologic correlation. AJR Am J Roentgenol, 2001; 176: 1255–1259.
Page D. L., Kidd T. E., Jr., Dupont W. D., Simpson J. F. and Rogers L. W. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol, 1991; 22: 1232–1239.
Kinne D. W. “Clinical management of lobular carcinoma in situ”. In, Breast Diseases, JR Harris, Hellman, S., Henderson, I.C., Kinne, D.W. ed., Philadelphia: Lippincott, 1991.
Andersen J. A. Lobular carcinoma in situ. A long-term follow-up in 52 cases. Acta Pathol Microbiol Scand [A], 1974; 82: 519–533.
Andersen J. A. Lobular carcinoma in situ of the breast. An approach to rational treatment. Cancer, 1977; 39: 2597–2602.
Page D. L., Schuyler P. A., Dupont W. D., Jensen R. A., Plummer W. D., Jr. and Simpson J. F. Atypical lobular hyperplasia as a unilateral predictor of breast cancer risk: a retrospective cohort study. Lancet, 2003; 361: 125–129.
Marshall L. M., Hunter D. J., Connolly J. L., Schnitt S. J., Byrne C., London S. J. and Colditz G. A. Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev, 1997; 6: 297–301.
Singletary S. E. and Greene F. L. Revision of breast cancer staging: the 6th edition of the TNM Classification. Semin Surg Oncol, 2003; 21: 53–59.
Sainsbury J. R., Anderson T. J. and Morgan D. A. ABC of breast diseases: breast cancer. Bmj, 2000; 321: 745–750.
McDonnell D. P. and Norris J. D. Connections and regulation of the human estrogen receptor. Science, 2002; 296: 1642–1644.
Tsai M. J. and O'Malley B. W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem, 1994; 63: 451–486.
Valagussa P., Bonadonna G. and Veronesi U. Patterns of relapse and survival following radical mastectomy. Analysis of 716 consecutive patients. Cancer, 1978; 41: 1170–1178.
Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet, 1998; 351: 1451–1467.
Menard S., Pupa S. M., Campiglio M. and Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene, 2003; 22: 6570–6578.
Fornier M., Munster P. and Seidman A. D. Update on the management of advanced breast cancer. Oncology (Huntingt), 1999; 13: 647–658; discussion 660, 663–664.
Clark G. M., Sledge G. W., Jr., Osborne C. K. and McGuire W. L. Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol, 1987; 5: 55–61.
Rutqvist L. E. and Wallgren A. Long-term survival of 458 young breast cancer patients. Cancer, 1985; 55: 658–665.
Fearon E. R. and Vogelstein B. A genetic model for colorectal tumorigenesis. Cell, 1990; 61: 759–767.
Vogelstein B. and Kinzler K. W. Cancer genes and the pathways they control. Nat Med, 2004; 10: 789–799.
Esteller M., Corn P. G., Baylin S. B. and Herman J. G. A gene hypermethylation profile of human cancer. Cancer Res, 2001; 61: 3225–3229.
Costello J. F., Fruhwald M. C., Smiraglia D. J., Rush L. J., Robertson G. P., Gao X., Wright F. A., Feramisco J. D., Peltomaki P., Lang J. C., Schuller D. E., Yu L., Bloomfield C. D., Caligiuri M. A., Yates A., Nishikawa R., Su Huang H., Petrelli N. J., Zhang X., O'Dorisio M. S., Held W. A., Cavenee W. K. and Plass C. Aberrant CpGisland methylation has non-random and tumour-type-specific patterns. Nat Genet, 2000; 24: 132–138.
Parrella P., Poeta M. L., Gallo A. P., Prencipe M., Scintu M., Apicella A., Rossiello R., Liguoro G., Seripa D., Gravina C., Rabitti C., Rinaldi M., Nicol T., Tommasi S., Paradiso A., Schittulli F., Altomare V. and Fazio V. M. Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors. Clin Cancer Res, 2004; 10: 5349–5354.
Nass S. J., Herman J. G., Gabrielson E., Iversen P. W., Parl F. F., Davidson N. E. and Graff J. R. Aberrant methylation of the estrogen receptor and E-cadherin 5′ CpG islands increases with malignant progression in human breast cancer. Cancer Res, 2000; 60: 4346–4348.
Esteller M., Fraga M. F., Guo M., Garcia-Foncillas J., Hedenfalk I., Godwin A. K., Trojan J., Vaurs-Barriere C., Bignon Y. J., Ramus S., Benitez J., Caldes T., Akiyama Y., Yuasa Y., Launonen V., Canal M. J., Rodriguez R., Capella G., Peinado M. A., Borg A., Aaltonen L. A., Ponder B. A., Baylin S. B. and Herman J. G. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet, 2001; 10: 3001–3007.
Bae Y. K., Brown A., Garrett E., Bornman D., Fackler M. J., Sukumar S., Herman J. G. and Gabrielson E. Hypermethylation in histologically distinct classes of breast cancer. Clin Cancer Res, 2004; 10: 5998–6005.
Nandi S., Guzman R. C. and Yang J. Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis. Proc Natl Acad Sci U S A, 1995; 92: 3650–7.
Kato S., Kitamoto T., Masuhiro Y. and Yanagisawa J. Molecular mechanism of a crosstalk between estrogen and growth-factor signaling pathways. Oncology, 1998; 55Suppl 1: 5–10.
Pike M. C., Spicer D. V., Dahmoush L. and Press M. F. Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev, 1993; 15: 17–35.
Group E. H. a. B. C. C. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst, 2002; 94: 606–616.
Henderson B. E. and Feigelson H. S. Hormonal carcinogenesis. Carcinogenesis, 2000; 21: 427–433.
Kato S. Estrogen receptor-mediated cross-talk with growth factor signaling pathways. Breast Cancer, 2001; 8: 3–9.
Yee D. and Lee A. V. Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia, 2000; 5: 107–115.
Hall J. M., Couse J. F. and Korach K. S. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem, 2001; 276: 36869–36872.
Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schutz G., Umesono K., Blumberg B., Kastner P., Mark M. and Chambon P. The nuclear receptor superfamily: the second decade. Cell, 1995; 83: 835–839.
McKenna N. J., Lanz R. B. and O'Malley B. W. Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev, 1999; 20: 321–44.
Mosselman S., Polman J. and Dijkema R. ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett, 1996; 392: 49–53.
Enmark E., Pelto-Huikko M., Grandien K., Lagercrantz S., Lagercrantz J., Fried G., Nordenskjold M. and Gustafsson J. A. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab, 1997; 82: 4258–4265.
Green S., Walter P., Greene G., Krust A., Goffin C., Jensen E., Scrace G., Waterfield M. and Chambon P. Cloning of the human oestrogen receptor cDNA. J Steroid Biochem, 1986; 24: 77–83.
Russo J., Ao X., Grill C. and Russo I. H. Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res Treat, 1999; 53: 217–227.
Petersen O. W., Hoyer P. E. and van Deurs B. Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Res, 1987; 47: 5748–5751.
Speirs V., Skliris G. P., Burdall S. E. and Carder P. J. Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol, 2002; 55: 371–374.
Kuiper G. G., Carlsson B., Grandien K., Enmark E., Haggblad J., Nilsson S. and Gustafsson J. A. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology, 1997; 138: 863–870.
Clarke R. B., Howell A., Potten C. S. and Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res, 1997; 57: 4987–4991.
Ethier S. P. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst, 1995; 87: 964–973.
Lippman M. E. and Dickson R. B. Growth control of normal and malignant breast epithelium. Prog Clin Biol Res, 1990; 354A: 147–178.
Ponglikitmongkol M., Green S. and Chambon P. Genomic organization of the human oestrogen receptor gene. Embo J, 1988; 7: 3385–3388.
Keaveney M., Klug J., Dawson M. T., Nestor P. V., Neilan J. G., Forde R. C. and Gannon F. Evidence for a previously unidentified upstream exon in the human oestrogen receptor gene. J Mol Endocrinol, 1991; 6: 111–115.
Grandien K. Determination of transcription start sites in the human estrogen receptor gene and identification of a novel, tissue-specific, estrogen receptor-mRNA isoform. Mol Cell Endocrinol, 1996; 116: 207–212.
Thompson D. A., McPherson L. A., Carmeci C., deConinck E. C. and Weigel R. J. Identification of two estrogen receptor transcripts with novel 5′ exons isolated from a MCF7 cDNA library. J Steroid Biochem Mol Biol, 1997; 62: 143–153.
Flouriot G., Griffin C., Kenealy M., Sonntag-Buck V. and Gannon F. Differentially expressed messenger RNA isoforms of the human estrogen receptor-alpha gene are generated by alternative splicing and promoter usage. Mol Endocrinol, 1998; 12: 1939–1954.
Piva R., Gambari R., Zorzato F., Kumar L. and del Senno L. Analysis of upstream sequences of the human estrogen receptor gene. Biochem Biophys Res Commun, 1992; 183: 996–1002.
Kos M., Reid G., Denger S. and Gannon F. Minireview: genomic organization of the human ERalpha gene promoter region. Mol Endocrinol, 2001; 15: 2057–2063.
Ottaviano Y. L., Issa J. P., Parl F. F., Smith H. S., Baylin S. B. and Davidson N. E. Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res, 1994; 54: 2552–2555.
Lapidus R. G., Ferguson A. T., Ottaviano Y. L., Parl F. F., Smith H. S., Weitzman S. A., Baylin S. B., Issa J. P. and Davidson N. E. Methylation of estrogen and progesterone receptor gene 5′ CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. Clin Cancer Res, 1996; 2: 805–810.
Lapidus R. G., Nass S. J., Butash K. A., Parl F. F., Weitzman S. A., Graff J. G., Herman J. G. and Davidson N. E. Mapping of ER gene CpG island methylation-specific polymerase chain reaction. Cancer Res, 1998; 58: 2515–2519.
Iwase H., Omoto Y., Iwata H., Toyama T., Hara Y., Ando Y., Ito Y., Fujii Y. and Kobayashi S. DNA methylation analysis at distal and proximal promoter regions of the oestrogen receptor gene in breast cancers. Br J Cancer, 1999; 80: 1982–1986.
Yoshida T., Eguchi H., Nakachi K., Tanimoto K., Higashi Y., Suemasu K., Iino Y., Morishita Y. and Hayashi S. Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of transacting factors. Carcinogenesis, 2000; 21: 2193–2201.
Penolazzi L., Lambertini E., Giordano S., Sollazzo V., Traina G., del Senno L. and Piva R. Methylation analysis of the promoter F of estrogen receptor alpha gene: effects on the level of transcription on human osteoblastic cells. J Steroid Biochem Mol Biol, 2004; 91: 1–9.
Zhao C., Lam E. W., Sunters A., Enmark E., De Bella M. T., Coombes R. C., Gustafsson J. A. and Dahlman-Wright K. Expression of estrogen receptor beta isoforms in normal breast epithelial cells and breast cancer: regulation by methylation. Oncogene, 2003; 22: 7600–7606.
Falette N. S., Fuqua S. A., Chamness G. C., Cheah M. S., Greene G. L. and McGuire W. L. Estrogen receptor gene methylation in human breast tumors. Cancer Res, 1990;50: 3974–3978.
Hori M., Iwasaki M., Yoshimi F., Asato Y. and Itabashi M. Hypermethylation of the Estrogen Receptor Alpha Gene Is Not Related to Lack of Receptor Protein in Human Breast Cancer. Breast Cancer, 1999; 6: 79–86.
Kay P. H., Hahnel R., Gunn H., Harmon D. and Song J. Hypermethylation of HpaII recognition sequences within the 5′ coding region of the estrogen receptor gene is not associated with estrogen receptor negativity in primary breast tumours. Anticancer Res, 1998; 18: 1709–1712.
Widschwendter M., Siegmund K. D., Muller H. M., Fiegl H., Marth C., Muller-Holzner E., Jones P. A. and Laird P. W. Association of breast cancer DNA methylation profiles with hormone receptor status and response to tamoxifen. Cancer Res, 2004; 64: 3807–3813.
Kastner P., Krust A., Turcotte B., Stropp U., Tora L., Gronemeyer H. and Chambon P. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. Embo J, 1990; 9: 1603–1614.
Sartorius C. A., Melville M. Y., Hovland A. R., Tung L., Takimoto G. S. and Horwitz K. B. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol, 1994; 8: 1347–1360.
McDonnell D. P., Shahbaz M. M., Vegeto E. and Goldman M. E. The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity. J Steroid Biochem Mol Biol, 1994; 48: 425–432.
Ferguson A. T., Lapidus R. G. and Davidson N. E. Demethylation of the progesterone receptor CpG island is not required for progesterone receptor gene expression. Oncogene, 1998; 17: 577–583.
Ki Hong W., Lippman S. M., Hittelman W. N. and Lotan R. Retinoid chemoprevention of aerodigestive cancer: from basic research to the clinic. Clin Cancer Res, 1995; 1:677–686.
Pastorino U., Infante M., Maioli M., Chiesa G., Buyse M., Firket P., Rosmentz N., Clerici M., Soresi E. and Valente M. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol, 1993; 11: 1216–1222.
Minucci S. and Pelicci P. G. Retinoid receptors in health and disease: co-regulators and the chromatin connection. Semin Cell Dev Biol, 1999; 10: 215–225.
Altucci L. and Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer, 2001; 1: 181–193.
de The H., Marchio A., Tiollais P. and Dejean A. Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes. Embo J 1989;8: 429–433.
Hoffmann B., Lehmann J. M., Zhang X. K., Hermann T., Husmann M., Graupner G. and Pfahl M. A retinoic acid receptor-specific element controls the retinoic acid receptor-beta promoter. Mol Endocrinol, 1990; 4: 1727–1736.
Widschwendter M., Berger J., Hermann M., Muller H. M., Amberger A., Zeschnigk M., Widschwendter A., Abendstein B., Zeimet A. G., Daxenbichler G. and Marth C. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst, 2000; 92: 826–832.
Widschwendter M., Berger J., Muller H. M., Zeimet A. G. and Marth C. Epigenetic downregulation of the retinoic acid receptor-beta2 gene in breast cancer. J Mammary Gland Biol Neoplasia, 2001; 6: 193–201.
Sirchia S. M., Ferguson A. T., Sironi E., Subramanyan S., Orlandi R., Sukumar S. and Sacchi N. Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor beta2 promoter in breast cancer cells. Oncogene, 2000; 19: 1556–1563.
Arapshian A., Kuppumbatti Y. S. and Mira-y-Lopez R. Methylation of conserved CpG sites neighboring the beta retinoic acid response element may mediate retinoic acid receptor beta gene silencing in MCF-7 breast cancer cells. Oncogene, 2000; 19: 4066–4070.
Bovenzi V., Le N. L., Cote S., Sinnett D., Momparler L. F. and Momparler R. L. DNA methylation of retinoic acid receptor beta in breast cancer and possible therapeutic role of 5-aza-2′-deoxycytidine. Anticancer Drugs, 1999; 10: 471–476.
Mehrotra J., Vali M., McVeigh M., Kominsky S. L., Fackler M. J., Lahti-Domenici J., Polyak K., Sacchi N., Garrett-Mayer E., Argani P. and Sukumar S. Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin Cancer Res, 2004; 10: 3104–3109.
Di Croce L., Raker V. A., Corsaro M., Fazi F., Fanelli M., Faretta M., Fuks F., Lo Coco F., Kouzarides T., Nervi C., Minucci S. and Pelicci P. G. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science, 2002; 295: 1079–1082.
O'shea P. J. and Williams G. R. Insight into the physiological actions of thyroid hormone receptors from genetically modified mice. J Endocrinol, 2002; 175: 553–570.
Li Z., Meng Z. H., Chandrasekaran R., Kuo W. L., Collins C. C., Gray J. W. and Dairkee S. H. Biallelic inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer. Cancer Res, 2002; 62: 1939–1943.
Yan P. S., Shi H., Rahmatpanah F., Hsiau T. H., Hsiau A. H., Leu Y. W., Liu J. C. and Huang T. H. Differential distribution of DNA methylation within the RASSF1A CpG island in breast cancer. Cancer Res, 2003; 63: 6178–6186.
McCormick F. Signal transduction. How receptors turn Ras on. Nature, 1993; 363: 15–16.
Serrano M., Lin A. W., McCurrach M. E., Beach D. and Lowe S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell, 1997; 88: 593–602.
Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev, 1998; 8: 49–54.
Burbee D. G., Forgacs E., Zochbauer-Muller S., Shivakumar L., Fong K., Gao B., Randle D., Kondo M., Virmani A., Bader S., Sekido Y., Latif F., Milchgrub S., Toyooka S., Gazdar A. F., Lerman M. I., Zabarovsky E., White M. and Minna J. D. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst, 2001; 93: 691–699.
Dammann R., Yang G. and Pfeifer G. P. Hypermethylation of the cpG island of Ras association domain family 1A (RASSF1A), a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers. Cancer Res, 2001; 61: 3105–3109.
Fackler M. J., McVeigh M., Evron E., Garrett E., Mehrotra J., Polyak K., Sukumar S. and Argani P. DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma. Int J Cancer, 2003; 107: 970–975.
Fackler M. J., McVeigh M., Mehrotra J., Blum M. A., Lange J., Lapides A., Garrett E., Argani P. and Sukumar S. Quantitative multiplex methylation-specific PCR assay for the detection of promoter hypermethylation in multiple genes in breast cancer. Cancer Res 2004; 64: 4442–4452.
Lehmann U., Langer F., Feist H., Glockner S., Hasemeier B. and Kreipe H. Quantitative assessment of promoter hypermethylation during breast cancer development. Am J Pathol, 2002; 160: 605–612.
Vos M. D., Ellis C. A., Bell A., Birrer M. J. and Clark G. J. Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. J Biol Chem, 2000; 275: 35669–33672.
Chen H., Pong R. C., Wang Z. and Hsieh J. T. Differential regulation of the human gene DAB2IP in normal and malignant prostatic epithelia: cloning and characterization. Genomics, 2002; 79: 573–581.
Wang Z., Tseng C. P., Pong R. C., Chen H., McConnell J. D., Navone N. and Hsieh J. T. The mechanism of growth-inhibitory effect of DOC-2/DAB2 in prostate cancer. Characterization of a novel GTPase-activating protein associated with N-terminal domain of DOC-2/DAB2. J Biol Chem, 2002; 277: 12622–12631.
Dote H., Toyooka S., Tsukuda K., Yano M., Ouchida M., Doihara H., Suzuki M., Chen H., Hsieh J. T., Gazdar A. F. and Shimizu N. Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer. Clin Cancer Res, 2004; 10: 2082–2089.
Sutherland K. D., Lindeman G. J., Choong D. Y., Wittlin S., Brentzell L., Phillips W., Campbell I. G. and Visvader J. E. Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Oncogene, 2004; 23: 7726–7733.
Hirano T., Ishihara K. and Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene, 2000; 19: 2548–2556.
Benson J. R. Role of transforming growth factor beta in breast carcinogenesis. Lancet Oncol, 2004; 5: 229–239.
Arteaga C. L., Tandon A. K., Von Hoff D. D. and Osborne C. K. Transforming growth factor beta: potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells. Cancer Res, 1988; 48: 3898–3904.
Kalkhoven E., Roelen B. A., de Winter J. P., Mummery C. L., van den Eijnden-van Raaij A. J., van der Saag P. T. and van der Burg B. Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines. Cell Growth Differ, 1995; 6: 1151–1161.
Sun L., Wu G., Willson J. K., Zborowska E., Yang J., Rajkarunanayake I., Wang J., Gentry L. E., Wang X. F. and Brattain M. G. Expression of transforming growth factor beta type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells. J Biol Chem, 1994; 269: 26449–2655.
Ammanamanchi S., Kim S. J., Sun L. Z. and Brattain M. G. Induction of transforming growth factor-beta receptor type II expression in estrogen receptor-positive breast cancer cells through SP1 activation by 5-aza-2′-deoxycytidine. J Biol Chem, 1998; 273: 16527–16534.
Ammanamanchi S. and Brattain M. G. Restoration of transforming growth factor-beta signaling through receptor RI induction by histone deacetylase activity inhibition in breast cancer cells. J Biol Chem, 2004; 279: 32620–3265.
Yu Y., Xu F., Peng H., Fang X., Zhao S., Li Y., Cuevas B., Kuo W. L., Gray J. W., Siciliano M., Mills G. B. and Bast R. C., Jr. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci U S A, 1999; 96: 214–219.
Yu Y., Fujii S., Yuan J., Luo R. Z., Wang L., Bao J., Kadota M., Oshimura M., Dent S. R., Issa J. P. and Bast R. C., Jr. Epigenetic regulation of ARHI in breast and ovarian cancer cells. Ann N Y Acad Sci, 2003; 983: 268–277.
Yuan J., Luo R. Z., Fujii S., Wang L., Hu W., Andreeff M., Pan Y., Kadota M., Oshimura M., Sahin A. A., Issa J. P., Bast R. C., Jr. and Yu Y. Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer Res, 2003; 63: 4174–4180.
Wang L., Hoque A., Luo R. Z., Yuan J., Lu Z., Nishimoto A., Liu J., Sahin A. A., Lippman S. M., Bast R. C., Jr. and Yu Y. Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clin Cancer Res, 2003; 9: 3660–3666.
Hisatomi H., Nagao K., Wakita K. and Kohno N. ARHI/NOEY2 inactivation may be important in breast tumor pathogenesis. Oncology, 2002; 62: 136–140.
Krop I. E., Sgroi D., Porter D. A., Lunetta K. L., LeVangie R., Seth P., Kaelin C. M., Rhei E., Bosenberg M., Schnitt S., Marks J.R., Pagon Z., Belina D., Razumovic J. and Polyak K. HIN-1, a putative cytokine highly expressed in normal but not cancerous mammary epithelial cells. Proc Natl Acad Sci U S A, 2001; 98: 9796–9801.
Krop I., Maguire P., Lahti-Domenici J., Lodeiro G., Richardson A., Johannsdottir H. K., Nevanlinna H., Borg A., Gelman R., Barkardottir R. B., Lindblom A. and Polyak K. Lack of HIN-1 methylation in BRCA1-linked and “BRCA1-like” breast tumors. Cancer Res, 2003; 63: 2024–2027.
Busslinger M., Klix N., Pfeffer P., Graninger P. G. and Kozmik Z. Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma. Proc Natl Acad Sci U S A, 1996; 93: 6129–6134.
Stapleton P., Weith A., Urbanek P., Kozmik Z. and Busslinger M. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nat Genet, 1993; 3: 292–298.
Palmisano W. A., Crume K. P., Grimes M. J., Winters S. A., Toyota M., Esteller M., Joste N., Baylin S. B. and Belinsky S. A. Aberrant promoter methylation of the transcription factor genes PAX5 alpha and beta in human cancers. Cancer Res, 2003; 63: 4620–4625.
Ledbetter J. A., Rabinovitch P. S., June C. H., Song C. W., Clark E. A. and Uckun F. M. Antigen-independent regulation of cytoplasmic calcium in B cells with a 12-kDa Bcell growth factor and anti-CD19. Proc Natl Acad Sci U S A, 1988; 85: 1897–1901.
Pardee A. B. G1 events and regulation of cell proliferation. Science, 1989; 246: 603–608.
Sherr C. J. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res, 2000; 60: 3689–3695.
Du Y., Carling T., Fang W., Piao Z., Sheu J. C. and Huang S. Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. Cancer Res, 2001; 61: 8094–8099.
Abbondanza C., Medici N., Nigro V., Rossi V., Gallo L., Piluso G., Belsito A., Roscigno A., Bontempo P., Puca A. A., Molinari A. M., Moncharmont B. and Puca G. A. The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action. Proc Natl Acad Sci U S A, 2000; 97: 3130–3135.
Carling T., Kim K. C., Yang X. H., Gu J., Zhang X. K. and Huang S. A histone methyltransferase is required for maximal response to female sex hormones. Mol Cell Biol, 2004; 24: 7032–7042.
Meyyappan M., Atadja P. W. and Riabowol K. T. Regulation of gene expression and transcription factor binding activity during cellular aging. Biol Signals 1996; 5: 130–138.
Meyyappan M., Wong H., Hull C. and Riabowol K. T. Increased expression of cyclin D2 during multiple states of growth arrest in primary and established cells. Mol Cell Biol, 1998;, 18: 3163–3172.
Evron E., Umbricht C. B., Korz D., Raman V., Loeb D. M., Niranjan B., Buluwela L., Weitzman S. A., Marks J. and Sukumar S. Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res, 2001; 61: 2782–2787.
Virmani A., Rathi A., Heda S., Sugio K., Lewis C., Tonk V., Takahashi T., Roth J. A., Minna J. D., Euhus D. M. and Gazdar A. F. Aberrant methylation of the cyclin D2 promoter in primary small cell, nonsmall cell lung and breast cancers. Int J Cancer, 2003; 107: 341–345.
Brenner A. J., Paladugu A., Wang H., Olopade O. I., Dreyling M. H. and Aldaz C. M. Preferential loss of expression of p16(INK4a) rather than p19(ARF) in breast cancer. Clin Cancer Res, 1996; 2: 1993–1998.
Berns E. M., Klijn J. G., Smid M., van Staveren I. L., Gruis N. A. and Foekens J. A. Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. Br J Cancer, 1995; 72: 964–967.
Calvano J. E., Rush E. B., Tan L. K., Rosen P. P., Borgen P. I. and Van Zee K. J. Absence of p16 gene (CDKN2) deletions in microdissected primary breast carcinoma specimens. Ann Surg Oncol, 1997;, 4: 416–420.
Quesnel B., Fenaux P., Philippe N., Fournier J., Bonneterre J., Preudhomme C. and Peyrat J. P. Analysis of p16 gene deletion and point mutation in breast carcinoma. Br J Cancer, 1995; 72: 351–353.
Gorgoulis V. G., Koutroumbi E. N., Kotsinas A., Zacharatos P., Markopoulos C., Giannikos L., Kyriakou V., Voulgaris Z., Gogas I. and Kittas C. Alterations of p16-pRb pathway and chromosome locus 9p21–22 in sporadic invasive breast carcinomas. Mol Med, 1998; 4: 807–822.
Borg A., Sandberg T., Nilsson K., Johannsson O., Klinker M., Masback A., Westerdahl J., Olsson H. and Ingvar C. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst, 2000; 92: 1260–1266.
Herman J. G., Merlo A., Mao L., Lapidus R. G., Issa J. P., Davidson N. E., Sidransky D. and Baylin S. B. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res, 1995; 55: 4525–4530.
Woodcock D. M., Linsenmeyer M. E., Doherty J. P. and Warren W. D. DNA methylation in the promoter region of the p16 (CDKN2/MTS-1/INK4A) gene in human breast tumours. Br J Cancer, 1999; 79: 251–256.
Silva J., Silva J. M., Dominguez G., Garcia J. M., Cantos B., Rodriguez R., Larrondo F. J., Provencio M., Espana P. and Bonilla F. Concomitant expression of p16INK4a and p14ARF in primary breast cancer and analysis of inactivation mechanisms. J Pathol, 2003; 199: 289–297.
Foster S. A., Wong D. J., Barrett M. T. and Galloway D. A. Inactivation of p16 in human mammary epithelial cells by CpG island methylation. Mol Cell Biol, 1998; 18: 1793–1801.
Crawford Y. G., Gauthier M. L., Joubel A., Mantei K., Kozakiewicz K., Afshari C. A. and Tlsty T. D. Histologically normal human mammary epithelia with silenced p16(INK4a) overexpress COX-2, promoting a premalignant program. Cancer Cell, 2004; 5: 263–273.
Holst C. R., Nuovo G. J., Esteller M., Chew K., Baylin S. B., Herman J. G. and Tlsty T. D. Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res, 2003; 63: 1596–1601.
Hui R., Macmillan R. D., Kenny F. S., Musgrove E. A., Blamey R. W., Nicholson R. I., Robertson J. F. and Sutherland R. L. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res, 2000; 6: 2777–2787.
Hajra K. M. and Liu J. R. Apoptosome dysfunction in human cancer. Apoptosis, 2004; 9: 691–704.
Pan G., O'Rourke K., Chinnaiyan A. M., Gentz R., Ebner R., Ni J. and Dixit V. M. The receptor for the cytotoxic ligand TRAIL. Science, 1997; 276: 111–113.
Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer, 2002; 2: 420–430.
Ashkenazi A. and Dixit V. M. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol, 1999; 11: 255–260.
Shivapurkar N., Toyooka S., Toyooka K. O., Reddy J., Miyajima K., Suzuki M., Shigematsu H., Takahashi T., Parikh G., Pass H. I., Chaudhary P. M. and Gazdar A. F. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer, 2004; 109: 786–792.
Chaudhary P. M., Eby M., Jasmin A., Bookwalter A., Murray J. and Hood L. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity, 1997; 7: 821–830.
Schneider P., Thome M., Burns K., Bodmer J. L., Hofmann K., Kataoka T., Holler N. and Tschopp J. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity, 1997; 7: 831–836.
Cohen G. M. Caspases: the executioners of apoptosis. Biochem J, 1997; 326 (Pt 1): 1–16.
Masumoto J., Taniguchi S., Ayukawa K., Sarvotham H., Kishino T., Niikawa N., Hidaka E., Katsuyama T., Higuchi T. and Sagara J. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem, 1999; 274: 33835–33838.
Conway K. E., McConnell B. B., Bowring C. E., Donald C. D., Warren S. T. and Vertino P. M. TMS1, a novel proapoptotic caspase recruitment domain protein, is a target of methylation-induced gene silencing in human breast cancers. Cancer Res, 2000; 60: 6236–6242.
Virmani A., Rathi A., Sugio K., Sathyanarayana U. G., Toyooka S., Kischel F. C., Tonk V., Padar A., Takahashi T., Roth J. A., Euhus D. M., Minna J. D. and Gazdar A. F. Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer. Int J Cancer, 2003; 106: 198–204.
Levine J. J., Stimson-Crider K. M. and Vertino P. M. Effects of methylation on expression of TMS1/ASC in human breast cancer cells. Oncogene, 2003; 22: 3475–3488.
Yokoyama T., Sagara J., Guan X., Masumoto J., Takeoka M., Komiyama Y., Miyata K., Higuchi K. and Taniguchi S. Methylation of ASC/TMS1, a proapoptotic gene responsible for activating procaspase-1, in human colorectal cancer. Cancer Lett, 2003; 202: 101–108.
Guan X., Sagara J., Yokoyama T., Koganehira Y., Oguchi M., Saida T. and Taniguchi S. ASC/TMS1, a caspase-1 activating adaptor, is downregulated by aberrant methylation in human melanoma. Int J Cancer, 2003; 107: 202–208.
Pharoah P. D., Day N. E. and Caldas C. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer, 1999; 80: 1968–1973.
Kang J. H., Kim S. J., Noh D. Y., Park I. A., Choe K. J., Yoo O. J. and Kang H. S. Methylation in the p53 promoter is a supplementary route to breast carcinogenesis: correlation between CpG methylation in the p53 promoter and the mutation of the p53 gene in the progression from ductal carcinoma in situ to invasive ductal carcinoma. Lab Invest, 2001; 81: 573–579.
Chene P. Inhibition of the p53-MDM2 interaction: targeting a protein-protein interface. Mol Cancer Res, 2004; 2: 20–28.
Zhang H. G., Wang J., Yang X., Hsu H. C. and Mountz J. D. Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene, 2004; 23: 2009–2015.
Quelle D. E., Zindy F., Ashmun R. A. and Sherr C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell, 1995; 83: 993–1000.
Kamijo T., Zindy F., Roussel M. F., Quelle D. E., Downing J. R., Ashmun R. A., Grosveld G. and Sherr C. J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell, 1997; 91: 649–659.
Mao L., Merlo A., Bedi G., Shapiro G. I., Edwards C. D., Rollins B. J. and Sidransky D. A novel p16INK4A transcript. Cancer Res, 1995; 55: 2995–2997.
Esteller M., Cordon-Cardo C., Corn P. G., Meltzer S. J., Pohar K. S., Watkins D. N., Capella G., Peinado M. A., Matias-Guiu X., Prat J., Baylin S. B. and Herman J. G. p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res, 2001; 61: 2816–2821.
Evron E., Dooley W. C., Umbricht C. B., Rosenthal D., Sacchi N., Gabrielson E., Soito A. B., Hung D. T., Ljung B., Davidson N. E. and Sukumar S. Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR. Lancet, 2001; 357: 1335–1336.
Nishizaki M., Sasaki J., Fang B., Atkinson E. N., Minna J. D., Roth J. A. and Ji L. Synergistic tumor suppression by coexpression of FHIT and p53 coincides with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-small cell lung cancer cells. Cancer Res, 2004; 64: 5745–5752.
Ingvarsson S. FHIT alterations in breast cancer. Semin Cancer Biol, 2001; 11: 361–366.
Zochbauer-Muller S., Fong K. M., Maitra A., Lam S., Geradts J., Ashfaq R., Virmani A. K., Milchgrub S., Gazdar A. F. and Minna J. D. 5′ CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. Cancer Res, 2001; 61: 3581–3585.
Yang Q., Nakamura M., Nakamura Y., Yoshimura G., Suzuma T., Umemura T., Shimizu Y., Mori I., Sakurai T. and Kakudo K. Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer. Clin Cancer Res, 2002; 8: 2890–2893.
Raman V., Martensen S. A., Reisman D., Evron E., Odenwald W. F., Jaffee E., Marks J. and Sukumar S. Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature, 2000; 405: 974–978.
Chen H., Chung S. and Sukumar S. HOXA5-induced apoptosis in breast cancer cells is mediated by caspases 2 and 8. Mol Cell Biol, 2004; 24: 924–935.
Chan T. A., Hermeking H., Lengauer C., Kinzler K. W. and Vogelstein B. 14-3-3 Sigma is required to prevent mitotic catastrophe after DNA damage. Nature, 1999; 401: 616–620.
Ferguson A. T., Evron E., Umbricht C. B., Pandita T. K., Chan T. A., Hermeking H., Marks J. R., Lambers A. R., Futreal P. A., Stampfer M. R. and Sukumar S. High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. Proc Natl Acad Sci U S A, 2000; 97: 6049–6054.
Umbricht C. B., Evron E., Gabrielson E., Ferguson A., Marks J. and Sukumar S. Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer. Oncogene, 2001; 20: 3348–3353.
Guerardel C., Deltour S., Pinte S., Monte D., Begue A., Godwin A. K. and Leprince D. Identification in the human candidate tumor suppressor gene HIC-1 of a new major alternative TATA-less promoter positively regulated by p53. J Biol Chem, 2001; 276: 3078–3089.
Wales M. M., Biel M. A., el Deiry W., Nelkin B. D., Issa J. P., Cavenee W. K., Kuerbitz S. J. and Baylin S. B. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med, 1995; 1: 570–577.
Rathi A., Virmani A. K., Harada K., Timmons C. F., Miyajima K., Hay R. J., Mastrangelo D., Maitra A., Tomlinson G. E. and Gazdar A. F. Aberrant methylation of the HIC1 promoter is a frequent event in specific pediatric neoplasms. Clin Cancer Res, 2003; 9: 3674–3678.
Rathi A., Virmani A. K., Schorge J. O., Elias K. J., Maruyama R., Minna J. D., Mok S. C., Girard L., Fishman D. A. and Gazdar A. F. Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin Cancer Res, 2002; 8: 3324–33231.
Rood B. R., Zhang H., Weitman D. M. and Cogen P. H. Hypermethylation of HIC-1 and 17p allelic loss in medulloblastoma. Cancer Res, 2002; 62: 3794–3797.
Fujii H., Biel M. A., Zhou W., Weitzman S. A., Baylin S. B. and Gabrielson E. Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer. Oncogene, 1998; 16: 2159–2164.
Parrella P., Scintu M., Prencipe M., Poeta M. L., Gallo A. P., Rabitti C., Rinaldi M., Tommasi S., Paradiso A., Schittulli F., Valori V. M., Toma S., Altomare V. and Fazio V. M. HIC1 promoter methylation and 17p13.3 allelic loss in invasive ductal carcinoma of the breast. Cancer Lett, 2004.
Chen W. Y., Zeng X., Carter M. G., Morrell C. N., Chiu Yen R. W., Esteller M., Watkins D. N., Herman J. G., Mankowski J. L. and Baylin S. B. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet, 2003; 33: 197–202.
Waite K. A. and Eng C. Protean PTEN: form and function. Am J Hum Genet, 2002; 70: 829–844.
Marsh D. J., Dahia P. L., Zheng Z., Liaw D., Parsons R., Gorlin R. J. and Eng C. Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet, 1997; 16: 333–334.
Liaw D., Marsh D. J., Li J., Dahia P. L., Wang S. I., Zheng Z., Bose S., Call K. M., Tsou H. C., Peacocke M., Eng C. and Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet, 1997; 16: 64–67.
Maehama T. and Dixon J. E. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol, 1999; 9: 125–128.
Maehama T. and Dixon J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem, 1998; 273: 13375–13378.
Lu Y., Lin Y. Z., LaPushin R., Cuevas B., Fang X., Yu S. X., Davies M. A., Khan H., Furui T., Mao M., Zinner R., Hung M. C., Steck P., Siminovitch K. and Mills G. B. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene, 1999; 18: 7034–45.
Stambolic V., Suzuki A., de la Pompa J. L., Brothers G. M., Mirtsos C., Sasaki T., Ruland J., Penninger J. M., Siderovski D. P. and Mak T. W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998; 95: 29–39.
Khan S., Kumagai T., Vora J., Bose N., Sehgal I., Koeffler P. H. and Bose S. PTEN promoter is methylated in a proportion of invasive breast cancers. Int J Cancer, 2004; 112: 407.
Varrault A., Bilanges B., Mackay D. J., Basyuk E., Ahr B., Fernandez C., Robinson D. O., Bockaert J. and Journot L. Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus. J Biol Chem, 2001; 276: 18653–18656.
Bilanges B., Varrault A., Basyuk E., Rodriguez C., Mazumdar A., Pantaloni C., Bockaert J., Theillet C., Spengler D. and Journot L. Loss of expression of the candidate tumor suppressor gene ZAC in breast cancer cell lines and primary tumors. Oncogene, 1999; 18: 3979–3988.
Abdollahi A., Pisarcik D., Roberts D., Weinstein J., Cairns P. and Hamilton T. C. LOT1 (PLAGL1/ZAC1), the candidate tumor suppressor gene at chromosome 6q24–25, is epigenetically regulated in cancer. J Biol Chem, 2003; 278: 6041–609.
Gonzalez A. D., Kaya M., Shi W., Song H., Testa J. R., Penn L. Z. and Filmus J. OCI-5/GPC3, a glypican encoded by a gene that is mutated in the Simpson-Golabi-Behmel overgrowth syndrome, induces apoptosis in a cell line-specific manner. J Cell Biol, 1998; 141: 1407–1414.
Xiang Y. Y., Ladeda V. and Filmus J. Glypican-3 expression is silenced in human breast cancer. Oncogene, 2001; 20: 7408–7412.
Chen C. M., Chen H. L., Hsiau T. H., Hsiau A. H., Shi H., Brock G. J., Wei S. H., Caldwell C. W., Yan P. S. and Huang T. H. Methylation target array for rapid analysis of CpG island hypermethylation in multiple tissue genomes. Am J Pathol, 2003; 163: 37–45.
Boland C. R., Thibodeau S. N., Hamilton S. R., Sidransky D., Eshleman J. R., Burt R. W., Meltzer S. J., Rodriguez-Bigas M. A., Fodde R., Ranzani G. N. and Srivastava S. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res, 1998; 58: 5248–5257.
Duesberg P., Rausch C., Rasnick D. and Hehlmann R. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci U S A, 1998; 95: 13692–13697.
Anbazhagan R., Fujii H. and Gabrielson E. Microsatellite instability is uncommon in breast cancer. Clin Cancer Res, 1999; 5: 839–844.
Adem C., Soderberg C. L., Cunningham J. M., Reynolds C., Sebo T. J., Thibodeau S. N., Hartmann L. C. and Jenkins R. B. Microsatellite instability in hereditary and sporadic breast cancers. Int J Cancer, 2003; 107: 580–582.
Muller A., Edmonston T. B., Corao D. A., Rose D. G., Palazzo J. P., Becker H., Fry R. D., Rueschoff J. and Fishel R. Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res, 2002; 62: 1014–1019.
Risinger J. I., Barrett J. C., Watson P., Lynch H. T. and Boyd J. Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer, 1996; 77: 1836–18343.
Yoon D. S., Wersto R. P., Zhou W., Chrest F. J., Garrett E. S., Kwon T. K. and Gabrielson E. Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am J Pathol, 2002; 161: 391–397.
Scully R., Chen J., Plug A., Xiao Y., Weaver D., Feunteun J., Ashley T. and Livingston D. M. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell, 1997; 88: 265–275.
Sharan S. K., Morimatsu M., Albrecht U., Lim D. S., Regel E., Dinh C., Sands A., Eichele G., Hasty P. and Bradley A. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature, 1997; 386: 804–810.
Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M. and Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science, 1994; 266: 66–71.
Neuhausen S. L. and Marshall C. J. Loss of heterozygosity in familial tumors from three BRCA1-linked kindreds. Cancer Res, 1994; 54: 6069–6072.
Beckmann M. W., Picard F., An H. X., van Roeyen C. R., Dominik S. I., Mosny D. S., Schnurch H. G., Bender H. G. and Niederacher D. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer, 1996; 73: 1220–126.
Rio P. G., Pernin D., Bay J. O., Albuisson E., Kwiatkowski F., De Latour M., Bernard-Gallon D. J. and Bignon Y. J. Loss of heterozygosity of BRCA1, BRCA2 and ATM genes in sporadic invasive ductal breast carcinoma. Int J Oncol, 1998; 13: 849–853.
Sorlie T., Andersen T. I., Bukholm I. and Borresen-Dale A. L. Mutation screening of BRCA1 using PTT and LOH analysis at 17q21 in breast carcinomas from familial and non-familial cases. Breast Cancer Res Treat, 1998; 48: 259–264.
Gonzalez R., Silva J. M., Dominguez G., Garcia J. M., Martinez G., Vargas J., Provencio M., Espana P. and Bonilla F. Detection of loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and BRCA2 loci in breast cancer: pathological correlations. Br J Cancer, 1999; 81: 503–509.
Katsama A., Sourvinos G., Zachos G. and Spandidos D. A. Allelic loss at the BRCA1, BRCA2 and TP53 loci in human sporadic breast carcinoma. Cancer Lett, 2000; 150: 165–170.
Futreal P. A., Liu Q., Shattuck-Eidens D., Cochran C., Harshman K., Tavtigian S., Bennett L. M., Haugen-Strano A., Swensen J., Miki Y. and et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science, 1994; 266: 120–122.
Papa S., Seripa D., Merla G., Gravina C., Giai M., Sismondi P., Rinaldi M., Serra A., Saglio G. and Fazio V. M. Identification of a possible somatic BRCA1 mutation affecting translation efficiency in an early-onset sporadic breast cancer patient. J Natl Cancer Inst, 1998; 90: 1011–1012.
Thompson M. E., Jensen R. A., Obermiller P. S., Page D. L. and Holt J. T. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet, 1995; 9: 444–450.
Yoshikawa K., Ogawa T., Baer R., Hemmi H., Honda K., Yamauchi A., Inamoto T., Ko K., Yazumi S., Motoda H., Kodama H., Noguchi S., Gazdar A. F., Yamaoka Y. and Takahashi R. Abnormal expression of BRCA1 and BRCA1-interactive DNA-repair proteins in breast carcinomas. Int J Cancer 2000;88: 28–36.
Magdinier F., Ribieras S., Lenoir G. M., Frappart L. and Dante R. Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. Oncogene, 1998; 17: 3169–3176.
Sourvinos G. and Spandidos D. A. Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. Biochem Biophys Res Commun, 1998; 245: 75–80.
Wilson C. A., Ramos L., Villasenor M. R., Anders K. H., Press M. F., Clarke K., Karlan B., Chen J. J., Scully R., Livingston D., Zuch R. H., Kanter M. H., Cohen S., Calzone F. J. and Slamon D. J. Localization of human BRCA1 and its loss in highgrade, non-inherited breast carcinomas. Nat Genet, 1999; 21: 236–240.
Khanna K. K. and Jackson S. P. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet, 2001; 27: 247–254.
Rice J. C., Massey-Brown K. S. and Futscher B. W. Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene, 1998; 17: 1807–1812.
Catteau A., Harris W. H., Xu C. F. and Solomon E. Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene, 1999; 18: 1957–1965.
Esteller M., Hamilton S. R., Burger P. C., Baylin S. B. and Herman J. G. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res, 1999; 59: 793–797.
Rice J. C., Ozcelik H., Maxeiner P., Andrulis I. and Futscher B. W. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis, 2000; 21: 1761–1765.
Hilton J. L., Geisler J. P., Rathe J. A., Hattermann-Zogg M. A., DeYoung B. and Buller R. E. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst, 2002; 94: 1396–1406.
Collins N., Wooster R. and Stratton M. R. Absence of methylation of CpG dinucleotides within the promoter of the breast cancer susceptibility gene BRCA2 in normal tissues and in breast and ovarian cancers. Br J Cancer, 1997; 76: 1150–1156.
Vo Q. N., Kim W. J., Cvitanovic L., Boudreau D. A., Ginzinger D. G. and Brown K. D. The ATM gene is a target for epigenetic silencing in locally advanced breast cancer. Oncogene, 2004; 58:9432–9437.
Swift M., Morrell D., Massey R. B. and Chase C. L. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med, 1991; 325: 1831–1836.
Inskip H. M., Kinlen L. J., Taylor A. M., Woods C. G. and Arlett C. F. Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia. Br J Cancer, 1999; 79: 1304–1307.
Olsen J. H., Hahnemann J. M., Borresen-Dale A. L., Brondum-Nielsen K., Hammarstrom L., Kleinerman R., Kaariainen H., Lonnqvist T., Sankila R., Seersholm N., Tretli S., Yuen J., Boice J. D., Jr. and Tucker M. Cancer in patients with ataxiatelangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst, 2001; 93: 121–127.
Chenevix-Trench G., Spurdle A. B., Gatei M., Kelly H., Marsh A., Chen X., Donn K., Cummings M., Nyholt D., Jenkins M. A., Scott C., Pupo G. M., Dork T., Bendix R., Kirk J., Tucker K., McCredie M. R., Hopper J. L., Sambrook J., Mann G. J. and Khanna K. K. Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 2002;94: 205–215.
Harden S. V., Sanderson H., Goodman S. N., Partin A. A., Walsh P. C., Epstein J. I. and Sidransky D. Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsies. J Natl Cancer Inst, 2003; 95: 1634–1637.
Esteller M., Corn P. G., Urena J. M., Gabrielson E., Baylin S. B. and Herman J. G. Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res, 1998; 58: 4515–4518.
Lee W. H., Morton R. A., Epstein J. I., Brooks J. D., Campbell P. A., Bova G. S., Hsieh W. S., Isaacs W. B. and Nelson W. G. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci U S A, 1994; 91: 11733–11737.
Tchou J. C., Lin X., Freije D., Isaacs W. B., Brooks J. D., Rashid A., De Marzo A. M., Kanai Y., Hirohashi S. and Nelson W. G. GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas. Int J Oncol, 2000; 16: 663–676.
Esteller M. Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer, 2000; 36: 2294–300.
Landis S. H., Murray T., Bolden S. and Wingo P. A. Cancer statistics, 1998. CA Cancer J Clin, 1998; 48: 6–29.
Boyd D. Invasion and metastasis. Cancer Metastasis Rev, 1996; 15: 77–89.
Bernards R. Cancer: cues for migration. Nature, 2003; 425: 247–248.
Welch D. R., Steeg P. S. and Rinker-Schaeffer C. W. Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis. Breast Cancer Res, 2000; 2: 408–416.
Behrens J. Cadherins and catenins: role in signal transduction and tumor progression. Cancer Metastasis Rev, 1999; 18: 15–30.
Meiners S., Brinkmann V., Naundorf H. and Birchmeier W. Role of morphogenetic factors in metastasis of mammary carcinoma cells. Oncogene, 1998; 16: 9–20.
Rasbridge S. A., Gillett C. E., Sampson S. A., Walsh F. S. and Millis R. R. Epithelial (E-) and placental (P-) cadherin cell adhesion molecule expression in breast carcinoma. J Pathol, 1993; 169: 245–250.
Daniel C. W., Strickland P. and Friedmann Y. Expression and functional role of E-and P-cadherins in mouse mammary ductal morphogenesis and growth. Dev Biol, 1995; 169: 511–519.
Heimann R., Lan F., McBride R. and Hellman S. Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin. Cancer Res, 2000; 60: 298–304.
Hunt N. C., Douglas-Jones A. G., Jasani B., Morgan J. M. and Pignatelli M. Loss of E-cadherin expression associated with lymph node metastases in small breast carcinomas. Virchows Arch, 1997; 430: 285–289.
Oka H., Shiozaki H., Kobayashi K., Inoue M., Tahara H., Kobayashi T., Takatsuka Y., Matsuyoshi N., Hirano S., Takeichi M. and et al. Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res, 1993; 53: 1696–1701.
Siitonen S. M., Kononen J. T., Helin H. J., Rantala I. S., Holli K. A. and Isola J. J. Reduced E-cadherin expression is associated with invasiveness and unfavorable prognosis in breast cancer. Am J Clin Pathol, 1996; 105: 394–402.
Gamallo C., Palacios J., Suarez A., Pizarro A., Navarro P., Quintanilla M. and Cano A. Correlation of E-cadherin expression with differentiation grade and histological type in breast carcinoma. Am J Pathol, 1993; 142: 987–993.
Moll R., Mitze M., Frixen U. H. and Birchmeier W. Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas. Am J Pathol 1993;143: 1731–1742.
Vos C. B., Cleton-Jansen A. M., Berx G., de Leeuw W. J., ter Haar N. T., van Roy F., Cornelisse C. J., Peterse J. L. and van de Vijver M. J. E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer, 1997; 76: 1131–1133.
Huiping C., Sigurgeirsdottir J. R., Jonasson J. G., Eiriksdottir G., Johannsdottir J. T., Egilsson V. and Ingvarsson S. Chromosome alterations and E-cadherin gene mutations in human lobular breast cancer. Br J Cancer, 1999; 81: 1103–1110.
Berx G., Cleton-Jansen A. M., Strumane K., de Leeuw W. J., Nollet F., van Roy F. and Cornelisse C. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene, 1996; 13: 1919–1925.
Berx G., Cleton-Jansen A. M., Nollet F., de Leeuw W. J., van de Vijver M., Cornelisse C. and van Roy F. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. Embo J, 1995; 14: 6107–6115.
Cleton-Jansen A. M. E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? Breast Cancer Res, 2002; 4: 5–8.
Sarrio D., Moreno-Bueno G., Hardisson D., Sanchez-Estevez C., Guo M., Herman J. G., Gamallo C., Esteller M. and Palacios J. Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability. Int J Cancer, 2003; 106: 208–215.
Graff J. R., Herman J. G., Lapidus R. G., Chopra H., Xu R., Jarrard D. F., Isaacs W. B., Pitha P. M., Davidson N. E. and Baylin S. B. E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res, 1995; 55: 5195–5199.
Graff J. R., Gabrielson E., Fujii H., Baylin S. B. and Herman J. G. Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem, 2000; 275: 2727–2732.
Wijnhoven B. P., Dinjens W. N. and Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg, 2000; 87: 992–1005.
Conacci-Sorrell M., Zhurinsky J. and Ben-Ze'ev A. The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest, 2002; 109: 987–991.
Yang S. Z., Kohno N., Yokoyama A., Kondo K., Hamada H. and Hiwada K. Decreased E-cadherin augments beta-catenin nuclear localization: studies in breast cancer cell lines. Int J Oncol, 2001; 18: 541–548.
Fearnhead N. S., Britton M. P. and Bodmer W. F. The ABC of APC. Hum Mol Genet, 2001; 10: 721–733.
Fearnhead N. S., Wilding J. L. and Bodmer W. F. Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. Br Med Bull, 2002; 64: 27–43.
Virmani A. K., Rathi A., Sathyanarayana U. G., Padar A., Huang C. X., Cunnigham H. T., Farinas A. J., Milchgrub S., Euhus D. M., Gilcrease M., Herman J., Minna J. D. and Gazdar A. F. Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter 1A in breast and lung carcinomas. Clin Cancer Res, 2001; 7: 1998–2004.
Mitchell P. J., Timmons P. M., Hebert J. M., Rigby P. W. and Tjian R. Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev, 1991; 5: 105–119.
Schorle H., Meier P., Buchert M., Jaenisch R. and Mitchell P. J. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature, 1996; 381: 235–238.
Batsche E., Muchardt C., Behrens J., Hurst H. C. and Cremisi C. RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol Cell Biol, 1998; 18: 3647–3658.
Hilger-Eversheim K., Moser M., Schorle H. and Buettner R. Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control. Gene, 2000; 260: 1–12.
Zeng Y. X., Somasundaram K. and el-Deiry W. S. AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression. Nat Genet, 1997; 15: 78–82.
Douglas D. B., Akiyama Y., Carraway H., Belinsky S. A., Esteller M., Gabrielson E., Weitzman S., Williams T., Herman J. G. and Baylin S. B. Hypermethylation of a small CpGuanine-rich region correlates with loss of activator protein-2alpha expression during progression of breast cancer. Cancer Res, 2004; 64: 1611–1620.
Adams J. C. and Watt F. M. Regulation of development and differentiation by the extracellular matrix. Development, 1993; 117: 1183–1198.
Bergstraesser L. M., Srinivasan G., Jones J. C., Stahl S. and Weitzman S. A. Expression of hemidesmosomes and component proteins is lost by invasive breast cancer cells. Am J Pathol, 1995; 147: 1823–1839.
Stahl S., Weitzman S. and Jones J. C. The role of laminin-5 and its receptors in mammary epithelial cell branching morphogenesis. J Cell Sci, 1997; 110 ( Pt 1): 55–63.
Martin K. J., Kwan C. P., Nagasaki K., Zhang X., O'Hare M. J., Kaelin C. M., Burgeson R. E., Pardee A. B. and Sager R. Down-regulation of laminin-5 in breast carcinoma cells. Mol Med, 1998; 4: 602–613.
Giannelli G. and Antonaci S. Biological and clinical relevance of Laminin-5 in cancer. Clin Exp Metastasis, 2000; 18: 439–443.
Sathyanarayana U. G., Padar A., Huang C. X., Suzuki M., Shigematsu H., Bekele B. N. and Gazdar A. F. Aberrant promoter methylation and silencing of laminin-5-encoding genes in breast carcinoma. Clin Cancer Res, 2003; 9: 6389–94.
Gomez D. E., Alonso D. F., Yoshiji H. and Thorgeirsson U. P. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol, 1997; 74: 111–22.
Bachman K. E., Herman J. G., Corn P. G., Merlo A., Costello J. F., Cavenee W. K., Baylin S. B. and Graff J. R. Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res, 1999; 59: 798–802.
Zou Z., Anisowicz A., Hendrix M. J., Thor A., Neveu M., Sheng S., Rafidi K., Seftor E. and Sager R. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science, 1994; 263: 526–529.
Maass N., Nagasaki K., Ziebart M., Mundhenke C. and Jonat W. Expression and regulation of tumor suppressor gene maspin in breast cancer. Clin Breast Cancer, 2002; 3: 281–287.
Domann F. E., Rice J. C., Hendrix M. J. and Futscher B. W. Epigenetic silencing of maspin gene expression in human breast cancers. Int J Cancer, 2000; 85: 805–810.
Futscher B. W., O'Meara M. M., Kim C. J., Rennels M. A., Lu D., Gruman L. M., Seftor R. E., Hendrix M. J. and Domann F. E. Aberrant methylation of the maspin promoter is an early event in human breast cancer. Neoplasia, 2004; 6: 380–389.
Cal S., Freije J. M., Lopez J. M., Takada Y. and Lopez-Otin C. ADAM 23/MDC3, a human disintegrin that promotes cell adhesion via interaction with the alphavbeta3 integrin through an RGD-independent mechanism. Mol Biol Cell, 2000; 11: 1457–1469.
Costa F. F., Verbisck N. V., Salim A. C., Ierardi D. F., Pires L. C., Sasahara R. M., Sogayar M. C., Zanata S. M., Mackay A., O'Hare M., Soares F., Simpson A. J. and Camargo A. A. Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors. Oncogene, 2004; 23: 1481–1488.
Heimann R., Ferguson D. J. and Hellman S. The relationship between nm23, angiogenesis, and the metastatic proclivity of node-negative breast cancer. Cancer Res, 1998; 58: 2766–2771.
Hartsough M. T., Clare S. E., Mair M., Elkahloun A. G., Sgroi D., Osborne C. K., Clark G. and Steeg P. S. Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition. Cancer Res, 2001; 61: 2320–2327.
Gruber A. D. and Pauli B. U. Tumorigenicity of human breast cancer is associated with loss of the Ca2+-activated chloride channel CLCA2. Cancer Res, 1999; 59: 5488–5491.
Li X., Cowell J. K. and Sossey-Alaoui K. CLCA2 tumour suppressor gene in 1p31 is epigenetically regulated in breast cancer. Oncogene, 2004; 23: 1474–1480.
Coopman P. J., Do M. T., Barth M., Bowden E. T., Hayes A. J., Basyuk E., Blancato J. K., Vezza P. R., McLeskey S. W., Mangeat P. H. and Mueller S. C. The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells. Nature, 2000; 406: 742–747.
Wang L., Duke L., Zhang P. S., Arlinghaus R. B., Symmans W. F., Sahin A., Mendez R. and Dai J. L. Alternative splicing disrupts a nuclear localization signal in spleen tyrosine kinase that is required for invasion suppression in breast cancer. Cancer Res, 2003; 63: 4724–4730.
Yuan Y., Mendez R., Sahin A. and Dai J. L. Hypermethylation leads to silencing of the SYK gene in human breast cancer. Cancer Res, 2001; 61: 5558–55561.
Yuan Y., Liu H., Sahin A. and Dai J. L. Reactivation of SYK expression by inhibition of DNA methylation suppresses breast cancer cell invasiveness. Int J Cancer, 2004; 113:654–659.
Dhar S., Bhargava R., Yunes M., Li B., Goyal J., Naber S. P., Wazer D. E. and 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, 2001; 7: 3393–8.
Goyal J., Smith K. M., Cowan J. M., Wazer D. E., Lee S. W. and Band V. The role for NES1 serine protease as a novel tumor suppressor. Cancer Res, 1998; 58: 4782–4786.
Li B., Goyal J., Dhar S., Dimri G., Evron E., Sukumar S., Wazer D. E. and Band V. CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression. Cancer Res, 2001; 61: 8014–8021.
Jia T., Liu Y. E., Liu J. and Shi Y. E. Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res, 1999; 59: 742–727.
Lu A., Gupta A., Li C., Ahlborn T. E., Ma Y., Shi E. Y. and Liu J. Molecular mechanisms for aberrant expression of the human breast cancer specific gene 1 in breast cancer cells: control of transcription by DNA methylation and intronic sequences. Oncogene, 2001; 20: 5173–5185.
Li Q., Ahuja N., Burger P. C. and Issa J. P. Methylation and silencing of the Thrombospondin-1 promoter in human cancer. Oncogene, 1999; 18: 3284–3289.
Chen L. M. and Chai K. X. Prostasin serine protease inhibits breast cancer invasiveness and is transcriptionally regulated by promoter DNA methylation. Int J Cancer, 2002; 97: 323–329.
Cavalli L. R., Urban C. A., Dai D., de Assis S., Tavares D. C., Rone J. D., Bleggi-Torres L. F., Lima R. S., Cavalli I. J., Issa J. P. and Haddad B. R. Genetic and epigenetic alterations in sentinel lymph nodes metastatic lesions compared to their corresponding primary breast tumors. Cancer Genet Cytogenet, 2003; 146: 33–40.
Widschwendter M. and Jones P. A. DNA methylation and breast carcinogenesis. Oncogene, 2002; 21: 5462–5482.
Barrows G. H., Anderson T. J., Lamb J. L. and Dixon J. M. Fine-needle aspiration of breast cancer. Relationship of clinical factors to cytology results in 689 primary malignancies. Cancer, 1986; 58: 1493–1498.
Pu R. T., Laitala L. E., Alli P. M., Fackler M. J., Sukumar S. and Clark D. P. Methylation profiling of benign and malignant breast lesions and its application to cytopathology. Mod Pathol, 2003; 16: 1095–1101.
Jeronimo C., Costa I., Martins M. C., Monteiro P., Lisboa S., Palmeira C., Henrique R., Teixeira M. R. and Lopes C. Detection of gene promoter hypermethylation in fine needle washings from breast lesions. Clin Cancer Res, 2003; 9: 3413–3417.
Krassenstein R., Sauter E., Dulaimi E., Battagli C., Ehya H., Klein-Szanto A. and Cairns P. Detection of breast cancer in nipple aspirate fluid by CpG island hypermethylation. Clin Cancer Res, 2004; 10: 28–32.
Wong I. H. Methylation profiling of human cancers in blood: molecular monitoring and prognostication (review). Int J Oncol, 2001; 19: 1319–1324.
Dulaimi E., Hillinck J., de C., II, Al-Saleem T. and Cairns P. Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res, 2004; 10: 6189–6193.
Muller H. M., Widschwendter A., Fiegl H., Ivarsson L., Goebel G., Perkmann E., Marth C. and Widschwendter M. DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res, 2003; 63: 7641–7645.
Muller H. M., Fiegl H., Widschwendter A. and Widschwendter M. Prognostic DNA methylation marker in serum of cancer patients. Ann N Y Acad Sci, 2004; 1022: 44–49.
Egger G., Liang G., Aparicio A. and Jones P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature, 2004; 429: 457–463.
Bender C. M., Pao M. M. and Jones P. A. Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res, 1998; 58: 95–101.
Segura-Pacheco B., Trejo-Becerril C., Perez-Cardenas E., Taja-Chayeb L., Mariscal I., Chavez A., Acuna C., Salazar A. M., Lizano M. and Duenas-Gonzalez A. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin Cancer Res, 2003; 9: 1596–1603.
Villar-Garea A., Fraga M. F., Espada J. and Esteller M. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res, 2003; 63: 4984–4989.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer
About this chapter
Cite this chapter
Parrella, P. (2005). CpG Island Hypermethylation in Breast Cancer Progression and Metastasis. In: Esteller, M. (eds) DNA Methylation, Epigenetics and Metastasis. Cancer Metastasis — Biology and Treatment, vol 7. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3642-6_5
Download citation
DOI: https://doi.org/10.1007/1-4020-3642-6_5
Publisher Name: Springer, Dordrecht
Print ISBN: 978-1-4020-3641-5
Online ISBN: 978-1-4020-3642-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)