Breast Cancer Research and Treatment

, Volume 122, Issue 3, pp 671–683 | Cite as

High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer

  • Gitana Maria Aceto
  • Angela Rosaria Solano
  • Maria Isabel Neuman
  • Serena Veschi
  • Annalisa Morgano
  • Sara Malatesta
  • Reinaldo Daniel Chacon
  • Carmen Pupareli
  • Mercedes Lombardi
  • Pasquale Battista
  • Antonio Marchetti
  • Renato Mariani-CostantiniEmail author
  • Ernesto Jorge Podestà
Preclinical study


Juvenile breast cancer is rare and poorly known. We studied a series of five breast cancer patients diagnosed within 25 years of age that included two adolescents, 12- and 15-years-old, and 3 young women, 21-, 21-, and 25-years-old, respectively. All cases were scanned for germline mutations along the entire BRCA1/2 coding sequences and TP53 exons 4–10, using protein truncation test, denaturing high performance liquid chromatography and direct sequencing. Paraffin-embedded primary tumors (available for 4/5 cases), and a distant metastasis (from the 15-years-old) were characterized for histological and molecular tumor subtype, human papilloma virus (HPV) types 16/18 E6 sequences and tumor-associated mutations in TP53 exons 5–8. A BRCA2 germline mutation (p.Ile2490Thr), previously reported in breast cancer and, as compound heterozygote, in Fanconi anemia, was identified in the 21-year-old patient diagnosed after pregnancy, negative for cancer family history. The tumor was not available for study. Only germline polymorphisms in BRCA1/2 and/or TP53 were detected in the other cases. The tumors of the 15- and 12-years-old were, respectively, classified as glycogen-rich carcinoma with triple negative subtype and as secretory carcinoma with basal subtype. The tumors of the 25-year-old and of the other 21-year-old were, respectively, diagnosed as infiltrating ductal carcinoma with luminal A subtype and as lobular carcinoma with luminal B subtype. No somatic TP53 mutations were found, but tumor-associated HPV 16 E6 sequences were retrieved from the 12- and 25-year-old, while both HPV 16 and HPV 18 E6 sequences were found in the tumor of the 15-year-old and in its associated metastasis. Blood from the 15- and 25-year-old, diagnosed with high-stage disease, resulted positive for HPV 16 E6. All the HPV-positive cases were homozygous for arginine at TP53 codon 72, a genotype associated with HPV-related cancer risk, and the tumors showed p16(INK4A) immunostaining, a marker of HPV-associated cancers. Notably menarche at 11 years was reported for the two adolescents, while the 25-year-old was diagnosed after pregnancy and breast-feeding. Our data suggest that high-risk HPV infection is involved in a subset of histopathologically heterogeneous juvenile breast carcinomas associated with menarche or pregnancy and breast-feeding. Furthermore we implicate BRCA2 in a juvenile breast carcinoma diagnosed at 21 years of age, 4 years after an early full-term pregnancy, in absence of cancer family history.


Juvenile breast cancer BRCA1 BRCA2 TP53 Mutation Human papilloma virus Reproductive factors 

HPV in juvenile breast cancer


Breast cancer


Juvenile breast cancer


Human papilloma virus


Laboratorio de Hormonas en la Regulacion y Diferenciacion Celular


Periodic acid-Schiff


Estrogen receptor


Progesterone receptor


Cytokeratin 5


Smooth muscle actin


Protein truncation test


Denaturing high performance liquid chromatography


Human Genome Variation Society


Polymerase chain reaction


Breast Cancer Information Core


Retinoblastoma protein


Cyclin-dependent kinase-4 inhibitor


International Agency for Research on Cancer

Supplementary material

10549_2009_596_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 40 kb)


  1. 1.
    Parkin DM (2004) International variation. Oncogene 23:6329–6340CrossRefPubMedGoogle Scholar
  2. 2.
    Levine PH, Pogo BG, Klouj A, Coronel S, Woodson K, Melana SM, Mourali N, Holland JF (2004) Increasing evidence for a human breast carcinoma virus with geographic differences. Cancer 101:721–726CrossRefPubMedGoogle Scholar
  3. 3.
    Tavani A, Braga C, La Vecchia C, Negri E, Russo A, Franceschi S (1997) Attributable risks for breast cancer in Italy: education, family history and reproductive and hormonal factors. Int J Cancer 70:159–163CrossRefPubMedGoogle Scholar
  4. 4.
    Hunter DJ, Willett WC (1993) Diet, body size, and breast cancer. Epidemiol Rev 15:110–132PubMedGoogle Scholar
  5. 5.
    Hulka BS, Moorman PG (2001) Breast cancer: hormones and other risk factors. Maturitas 38:103–113CrossRefPubMedGoogle Scholar
  6. 6.
    Dumitrescu RG, Cotarla I (2005) Understanding breast cancer risk—where do we stand in 2005? J Cell Mol Med 9:208–221CrossRefPubMedGoogle Scholar
  7. 7.
    Lagerros YT, Hsieh SF, Hsieh CC (2004) Physical activity in adolescence and young adulthood and breast cancer risk: a quantitative review. Eur J Cancer Prev 13:5–12CrossRefPubMedGoogle Scholar
  8. 8.
    Dehner LP, Hill DA, Deschryver K (1999) Pathology of the breast in children, adolescents, and young adults. Semin Diagn Pathol 16:235–247PubMedGoogle Scholar
  9. 9.
    Wilson M, Cranor ML, Rosen PP (1993) Papillary duct hyperplasia of the breast in children and young women. Mod Pathol 6:570–574PubMedGoogle Scholar
  10. 10.
    Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (2002) Cancer incidence in 5 continents, vol. 8 (IARC Scientific Publication No. 155). International Agency for Research on Cancer (IARC), Lyon, FranceGoogle Scholar
  11. 11.
    Medina D (2005) Mammary developmental fate and breast cancer risk. Endocr Relat Cancer 12:483–495CrossRefPubMedGoogle Scholar
  12. 12.
    Russo J, Balogh GA, Chen J, Fernandez SV, Fernbaugh R, Heulings R, Mailo DA, Moral R, Russo PA, Sheriff F, Vanegas JE, Wang R, Russo IH (2006) The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci 11:151–172CrossRefPubMedGoogle Scholar
  13. 13.
    Russo IH, Russo J (1998) Role of hormones in mammary cancer initiation and progression. J Mammary Gland Biol Neoplasia 3:49–61CrossRefPubMedGoogle Scholar
  14. 14.
    Hiraku Y, Yamashita N, Nishiguchi M, Kawanishi S (2001) Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation. Int J Cancer 92:333–337CrossRefPubMedGoogle Scholar
  15. 15.
    Hilakivi-Clarke L, de Assis S (2006) Fetal origins of breast cancer. Trends Endocrinol Metab 17:340–348CrossRefPubMedGoogle Scholar
  16. 16.
    Brooks GA, Stopfer JE, Erlichman J, Davidson R, Nathanson KL, Domchek SM (2006) Childhood cancer in families with and without BRCA1 or BRCA2 mutations ascertained at a high-risk breast cancer clinic. Cancer Biol Ther 5:1098–1102PubMedGoogle Scholar
  17. 17.
    Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71CrossRefPubMedGoogle Scholar
  18. 18.
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792CrossRefPubMedGoogle Scholar
  19. 19.
    Malkin D, Li FP, Strong LC et al (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238CrossRefPubMedGoogle Scholar
  20. 20.
    Lalloo F, Varley J, Moran A, Ellis D, O’Dair L, Pharoah P, Antoniou A, Hartley R, Shenton A, Seal S, Bulman B, Howell A, Gareth D, Evans R (2006) BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 42:1143–1150CrossRefPubMedGoogle Scholar
  21. 21.
    Liu Y, Klimberg VS, Andrews NR, Hicks CR, Peng H, Chiriva-Internati M, Henry-Tillman R (2001) Human papillomavirus DNA is present in a subset of unselected breast cancers. J Hum Virol 4:329–334PubMedGoogle Scholar
  22. 22.
    Pagano JS, Blaser M, Buendia M, Da Mania B, Khalili K, Raab-Traub N, Roizman B (2004) Infectious agents and cancer: criteria for a causal relation. Semin Cancer Biol 14:453–471CrossRefPubMedGoogle Scholar
  23. 23.
    Band V, Zajchowski D, Kulesa V, Sager R (1990) Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements. Proc Natl Acad Sci USA 87:463–467CrossRefPubMedGoogle Scholar
  24. 24.
    Damin AP, Karam R, Zettler CG, Caleffi M, Alexandre CO (2004) Evidence for an association of human papillomavirus and breast carcinomas. Breast Cancer Res Treat 84:131–137CrossRefPubMedGoogle Scholar
  25. 25.
    Di Lonardo A, Venuti A, Marcante ML (1992) Human papillomavirus in breast cancer. Breast Cancer Res Treat 21:95–100CrossRefPubMedGoogle Scholar
  26. 26.
    Hennig EM, Suo Z, Thoresen S, Holm R, Kvinnsland S, Nesland JM (1999) Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III). Breast Cancer Res Treat 53:121–135CrossRefPubMedGoogle Scholar
  27. 27.
    Muñoz N, Franceschi S, Bosetti C, Moreno V, Herrero R, Smith JS, Shah KV, Meijer CJ, Bosch FX (2002) Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. International Agency for Research on Cancer. Multicentric Cervical Cancer Study Group. Lancet 359:1093–1101CrossRefPubMedGoogle Scholar
  28. 28.
    Sethi S, Müller M, Schneider A, Blettner M, Smith E, Turek L, Wahrendorf J, Gissmann L, Chang-Claude J (1998) Serologic response to the E4, E6, and E7 proteins of human papillomavirus type 16 in pregnant women. Am J Obstet Gynecol 178:360–364CrossRefPubMedGoogle Scholar
  29. 29.
    Schwartsmann G (2001) Breast cancer in South America: challenges to improve early detection and medical management of a public health problem. J Clin Oncol 19(18 Suppl):118S–124SPubMedGoogle Scholar
  30. 30.
    Ellis IO, Schnitt SJ, Sastre-Garau X et al (2003) Invasive breast carcinoma. In: Tavassoli FA, Devilee P (eds) In pathology and genetics of the breast and female genital organs. IARC Press, Lyon, pp 13–59Google Scholar
  31. 31.
    Greene FL, Page DL, Fleming ID et al (2002) AJCC cancer staging manual, 6th edn. Springer, New YorkGoogle Scholar
  32. 32.
    Frierson HF Jr, Wolber RA, Berean KW et al (1995) Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol 103:195–198PubMedGoogle Scholar
  33. 33.
    Ottini L, Masala G, D’Amico C, Mancini B, Saieva C, Aceto G, Gestri D, Vezzosi V, Falchetti M, De Marco M, Paglierani M, Cama A, Bianchi S, Mariani-Costantini R, Palli D (2003) BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res 63:342–347PubMedGoogle Scholar
  34. 34.
    Soussi T (2000) The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci 910:121–137PubMedGoogle Scholar
  35. 35.
    Gross E, Arnold N, Pfeifer K, Bandick K, Kiechle M (2000) Identification of specific BRCA1 and BRCA2 variants by DHPLC. Hum Mutat 16:345–353CrossRefPubMedGoogle Scholar
  36. 36.
    Wagner T, Stoppa-Lyonnet D, Fleischmann E, Muhr D, Pagès S, Sandberg T, Caux V, Moeslinger R, Langbauer G, Borg A, Oefner P (1999) Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. Genomics 62:369–376CrossRefPubMedGoogle Scholar
  37. 37.
    Yamanoshita O, Kubota T, Hou J et al (2005) DHPLC is superior to SSCP in screening p53 mutations in esophageal cancer tissues. Int J Cancer 114:74–79CrossRefPubMedGoogle Scholar
  38. 38.
    Ng PC, Henikoff S (2002) Accounting for human polymorphisms predicted to affect protein function. Genome Res 12:436–446CrossRefPubMedGoogle Scholar
  39. 39.
    Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: A web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571CrossRefPubMedGoogle Scholar
  40. 40.
    Ottini L, Palli D, Falchetti M, D’Amico C, Amorosi A, Saieva C, Calzolari A, Cimoli F, Tatarelli C, De Marchis L, Masala G, Mariani-Costantini R, Cama A (1997) Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res 57:4523–4529PubMedGoogle Scholar
  41. 41.
    Mahdavinia M, Bishehsari F, Verginelli F, Cumashi A, Lattanzio R, Sotoudeh M, Ansari R, Semeraro D, Hormazdi M, Fakheri H, Rakhshani N, De Lellis L, Curia MC, Cama A, Piantelli M, Malekzadeh R, Iacobelli S, Mariani-Costantini R (2008) P53 mutations in colorectal cancer from northern Iran: Relationships with site of tumor origin, microsatellite instability and K-ras mutations. J Cell Physiol 216:543–550CrossRefPubMedGoogle Scholar
  42. 42.
    Morris BJ (2005) Cervical human papillomavirus screening by PCR: advantages of targeting the E6/E7 region. Clin Chem Lab Med 43:1171–1177CrossRefPubMedGoogle Scholar
  43. 43.
    Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100:8418–8423CrossRefPubMedGoogle Scholar
  44. 44.
    Aoki MN, da Silva do Amaral Herrera AC, Amarante MK, do Val Carneiro JL, Fungaro MH, Watanabe MA (2009) CCR5 and p53 codon 72 gene polymorphisms: implications in breast cancer development. Int J Mol Med 23:429–435PubMedGoogle Scholar
  45. 45.
    Scheurer ME, Tortolero-Luna G, Adler-Storthz K (2005) Human papillomavirus infection: biology, epidemiology, and prevention. Int J Gynecol Cancer 15:727–746CrossRefPubMedGoogle Scholar
  46. 46.
    Stoler MH (2000) Human papillomaviruses and cervical neoplasia: a model for carcinogenesis. Int J Gynecol Pathol 19:16–28CrossRefPubMedGoogle Scholar
  47. 47.
    Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, Petry U, Dallenbach-Hellweg G, Schmidt D, von Knebel Doeberitz M (2001) Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276–284CrossRefPubMedGoogle Scholar
  48. 48.
    Luft F, Klaes R, Nees M, Dürst M, Heilmann V, Melsheimer P, von Knebel Doeberitz M (2001) Detection of integrated papillomavirus sequences by ligation-mediated PCR (DIPS-PCR) and molecular characterization in cervical cancer cells. Int J Cancer 92:9–17CrossRefPubMedGoogle Scholar
  49. 49.
    Wentzensen N, Vinokurova S, von Knebel Doeberitz M (2004) Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res 64:3878–3884CrossRefPubMedGoogle Scholar
  50. 50.
    Kuroda H, Sakamoto G, Ohnisi K, Itoyama S (2005) Clinical and pathological features of glycogen-rich clear cell carcinoma of the breast. Breast Cancer 12:189–195CrossRefPubMedGoogle Scholar
  51. 51.
    Nonomura A, Kimura A, Mizukami Y, Nakamura S, Ohmura K, Watanabe Y, Tanimoto K, Ikegaki S (1995) Secretory carcinoma of the breast associated with juvenile papillomatosis in a 12-year-old girl. A case report. Acta Cytol 39:569–576PubMedGoogle Scholar
  52. 52.
    Rice HE, Acosta A, Brown RL, Gutierrez C, Alashari M, Mintequi D, Rodriguez A, Chavarrfa O, Azizkhan RG (2000) Juvenile papillomatosis of the breast in male infants: two case reports. Pediatr Surg Int 16:104–106CrossRefPubMedGoogle Scholar
  53. 53.
    Rosen PP (1997) Rosen’s breast pathology. Lippincott-Raven Publishers, Philadelphia, pp 441–447Google Scholar
  54. 54.
    Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T (1998) Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol 153:1741–1748PubMedGoogle Scholar
  55. 55.
    Ford D, Easton DF, Stratton M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62:676–689CrossRefPubMedGoogle Scholar
  56. 56.
    McClain MR, Nathanson KL, Palomaki GE, Haddow JE (2005) An evaluation of BRCA1 and BRCA2 founder mutations penetrance estimates for breast cancer among Ashkenazi Jewish women. Genet Med 7:34–39CrossRefPubMedGoogle Scholar
  57. 57.
    Veschi S, Aceto G, Scioletti AP, Gatta V, Palka G, Cama A, Mariani-Costantini R, Battista P, Calò V, Barbera F, Bazan V, Russo A, Stuppia L (2007) High prevalence of BRCA1 deletions in BRCAPRO-positive patients with high carrier probability. Ann Oncol 18(Suppl 6):vi86–vi92CrossRefPubMedGoogle Scholar
  58. 58.
    Palacios J, Robles-Frías MJ, Castilla MA, López-García MA, Benítez J (2008) The molecular pathology of hereditary breast cancer. Pathobiology 75:85–94CrossRefPubMedGoogle Scholar
  59. 59.
    Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95:1548–1551PubMedGoogle Scholar
  60. 60.
    Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 25:5832–5836CrossRefPubMedGoogle Scholar
  61. 61.
    Lee E, Ma H, McKean-Cowdin R, Van Den Berg D, Bernstein L, Henderson BE, Ursin G (2008) Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: results from a population-based study. Cancer Epidemiol Biomarkers Prev 17:3170–3178CrossRefPubMedGoogle Scholar
  62. 62.
    Andrieu N, Goldgar DE, Easton DF et al (2006) Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst 98:535–544CrossRefPubMedGoogle Scholar
  63. 63.
    Keinan-Boker L, Lerner-Geva L, Kaufman B, Meirow D (2008) Pregnancy-associated breast cancer. Isr Med Assoc J 10:722–727PubMedGoogle Scholar
  64. 64.
    Awadelkarim KD, Aceto G, Veschi S, Elhaj A, Morgano A, Mohamedani AA, Eltayeb EA, Abuidris D, Di Gioacchino M, Battista P, Verginelli F, Cama A, Elwali NE, Mariani-Costantini R (2007) BRCA1 and BRCA2 status in a Central Sudanese series of breast cancer patients: interactions with genetic, ethnic and reproductive factors. Breast Cancer Res Treat 102:189–199CrossRefPubMedGoogle Scholar
  65. 65.
    Matlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV (1987) Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 7:961–963PubMedGoogle Scholar
  66. 66.
    Pim D, Banks L (2004) p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int J Cancer 108:196–199CrossRefPubMedGoogle Scholar
  67. 67.
    Dumont P, Leu JI, Della Pietra AC III, George DL, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33:357–365CrossRefPubMedGoogle Scholar
  68. 68.
    Katiyar S, Thelma BK, Murthy NS, Hedau S, Jain N, Gopalkrishna V, Husain SA, Das BC (2003) Polymorphism of the p53 codon 72 Arg/Pro and the risk of HPV type 16/18-associated cervical and oral cancer in India. Mol Cell Biochem 252:117–124CrossRefPubMedGoogle Scholar
  69. 69.
    Siddique MM, Balram C, Fiszer-Maliszewska L, Aggarwal A, Tan A, Tan P, Soo KC, Sabapathy K (2005) Evidence for selective expression of the p53 codon 72 polymorphism: implications in cancer development. Cancer Epidemiol Biomarkers Prev 14:2245–2252CrossRefPubMedGoogle Scholar
  70. 70.
    Olivier M, Langerød A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bièche I, Varley J, Bignon Y, Uhrhammer N, Winqvist R, Jukkola-Vuorinen A, Niederacher D, Kato S, Ishioka C, Hainaut P, Børresen-Dale AL (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167CrossRefPubMedGoogle Scholar
  71. 71.
    Muñoz N, Castellsague X, de Gonzalez AB, Gissman L (2006) HPV in the etiology of human cancer. Vaccine 24:S1–S10CrossRefGoogle Scholar
  72. 72.
    Jeon S, Lambert PF (1995) Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci USA 92:1654–1658CrossRefPubMedGoogle Scholar
  73. 73.
    Vinokurova S, Wentzensen N, Einenkel J, Klaes R, Ziegert C, Melsheimer P, Sartor H, Horn LC, Höckel M, von Knebel Doeberitz M (2005) Clonal history of papillomavirus-induced dysplasia in the female lower genital tract. J Natl Cancer Inst 97:1816–1821CrossRefPubMedGoogle Scholar
  74. 74.
    International Agency for Research on Cancer (IARC) (1995) IARC monographs on the evaluation of carcinogenic risks to humans. Human papillomaviruses, vol 64. IARC, LyonGoogle Scholar
  75. 75.
    Ganguly N, Parihar SP (2009) Human papillomavirus E6 and E7 oncoproteins as risk factors for tumorigenesis. J Biosci 34:113–123 ReviewCrossRefPubMedGoogle Scholar
  76. 76.
    Woodman CB, Collins SI, Young LS (2007) The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 7:11–22CrossRefPubMedGoogle Scholar
  77. 77.
    Kroupis C, Markou A, Vourlidis N, Dionyssiou-Asteriou A, Lianidou ES (2006) Presence of high-risk human papillomavirus sequences in breast cancer tissues and association with histopathological characteristics. Clin Biochem 39:727–731CrossRefPubMedGoogle Scholar
  78. 78.
    Pornthanakasem W, Shotelersuk K, Termrungruanglert W, Voravud N, Niruthisard S, Mutirangura A (2001) Human papillomavirus DNA in plasma of patients with cervical cancer. BMC Cancer 1:2CrossRefPubMedGoogle Scholar
  79. 79.
    Samama B, Lipsker D, Boehm N (2006) p16 expression in relation to human papillomavirus in anogenital lesions. Hum Pathol 37:513–519CrossRefPubMedGoogle Scholar
  80. 80.
    Nindl I, Meyer T, Schmook T, Ulrich C, Ridder R, Audring H, Sterry W, Stockfleth E (2004) Human papillomavirus and overexpression of P16INK4a in nonmelanoma skin cancer. Dermatol Surg 30:409–414CrossRefPubMedGoogle Scholar
  81. 81.
    Hafkamp HC, Speel EJ, Haesevoets A, Bot FJ, Dinjens WN, Ramaekers FC, Hopman AH, Manni JJ (2003) A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8. Int J Cancer 107:394–400CrossRefPubMedGoogle Scholar
  82. 82.
    Klussmann JP, Gültekin E, Weissenborn SJ, Wieland U, Dries V, Dienes HP, Eckel HE, Pfister HJ, Fuchs PG (2003) Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol 162:747–753PubMedGoogle Scholar
  83. 83.
    Shai A, Pitot HC, Lambert PF (2008) p53 Loss synergizes with estrogen and papillomaviral oncogenes to induce cervical and breast cancers. Cancer Res 68:2622–2631CrossRefPubMedGoogle Scholar
  84. 84.
    Mammas IN, Sourvinos G, Spandidos DA (2009) Human papilloma virus (HPV) infection in children and adolescents. Eur J Pediatr 168:267–273CrossRefPubMedGoogle Scholar
  85. 85.
    Subhawong AP, Subhawong T, Nassar H, Kouprina N, Begum S, Vang R, Westra WH, Argani P (2009) Most basal-like breast carcinomas demonstrate the same Rb-/p16+ immunophenotype as the HPV-related poorly differentiated squamous cell carcinomas which they resemble morphologically. Am J Surg Pathol 33:163–175CrossRefPubMedGoogle Scholar
  86. 86.
    Herschkowitz JI, He X, Fan C, Perou CM (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10:R75CrossRefPubMedGoogle Scholar
  87. 87.
    Derenzini M, Donati G, Mazzini G, Montanaro L, Vici M, Ceccarelli C, Santini D, Taffurelli M, Treré D (2008) Loss of retinoblastoma tumor suppressor protein makes human breast cancer cells more sensitive to antimetabolite exposure. Clin Cancer Res 14:2199–2209CrossRefPubMedGoogle Scholar
  88. 88.
    Derenzini M, Brighenti E, Donati G, Vici M, Ceccarelli C, Santini D, Taffurelli M, Montanaro L, Treré D (2009) The p53-mediated sensitivity of cancer cells to chemotherapeutic agents is conditioned by the status of the retinoblastoma protein. J Pathol 219(3):373–382CrossRefPubMedGoogle Scholar
  89. 89.
    Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J (2009) Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 27:1992–1998CrossRefPubMedGoogle Scholar
  90. 90.
    Klussmann JP, Mooren JJ, Lehnen M, Claessen SM, Stenner M, Huebbers CU, Weissenborn SJ, Wedemeyer I, Preuss SF, Straetmans JM, Manni JJ, Hopman AH, Speel EJ (2009) Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications. Clin Cancer Res 15:1779–1786CrossRefPubMedGoogle Scholar
  91. 91.
    Beglin M, Melar-New M, Laimins L (2009) Human papillomaviruses and the interferon response. J Interferon Cytokine Res 29:629–635CrossRefPubMedGoogle Scholar
  92. 92.
    Critchley-Thorne RJ, Simons DL, Yan N, Miyahira AK, Dirbas FM, Johnson DL, Swetter SM, Carlson RW, Fisher GA, Koong A, Holmes S, Lee PP (2009) Impaired interferon signaling is a common immune defect in human cancer. Proc Natl Acad Sci USA 106:9010–9015CrossRefPubMedGoogle Scholar
  93. 93.
    Stanley M (2003) Genital human papillomavirus infections—current and prospective therapies. J Natl Cancer Inst Monographs 31:117–124PubMedGoogle Scholar
  94. 94.
    Trimble CL, Frazer IH (2009) Development of therapeutic HPV vaccines. Lancet Oncol 10:975–980CrossRefPubMedGoogle Scholar
  95. 95.
    Albers AE, Kaufmann AM (2009) Therapeutic human papillomavirus vaccination. Public Health Genomics 12:331–342CrossRefPubMedGoogle Scholar
  96. 96.
    Heng B, Glenn WK, Ye Y, Tran B, Delprado W, Lutze-Mann L, Whitaker NJ, Lawson JS (2009) Human papilloma virus is associated with breast cancer. Br J Cancer 101:1345–1350CrossRefPubMedGoogle Scholar
  97. 97.
    Lowy DR, Solomon D, Hildesheim A, Schiller JT, Schiffman M (2008) Human papillomavirus infection and the primary and secondary prevention of cervical cancer. Cancer 113(7 Suppl):1980–1993CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Gitana Maria Aceto
    • 1
    • 3
  • Angela Rosaria Solano
    • 4
  • Maria Isabel Neuman
    • 4
  • Serena Veschi
    • 1
    • 2
    • 3
  • Annalisa Morgano
    • 1
    • 2
  • Sara Malatesta
    • 5
  • Reinaldo Daniel Chacon
    • 6
  • Carmen Pupareli
    • 6
  • Mercedes Lombardi
    • 7
  • Pasquale Battista
    • 3
  • Antonio Marchetti
    • 5
  • Renato Mariani-Costantini
    • 1
    • 2
    Email author
  • Ernesto Jorge Podestà
    • 4
  1. 1.Unit of Molecular Pathology and GenomicsAging Research Center (CeSI) G. d’Annunzio University FoundationChietiItaly
  2. 2.Department of Oncology and NeurosciencesG. d’Annunzio UniversityChietiItaly
  3. 3.Department of Human Movement SciencesG. d’Annunzio UniversityChietiItaly
  4. 4.Laboratorio de Hormonas en la Regulacion y Diferenciacion Celular (HRDC), Instituto de Investigaciones Moleculares de Enfermedades Hormonales Neurodegenerativas y Oncologicas (IIMHNO), Departamento de Bioquímica, Facultad de MedicinaUniversidad de Buenos AiresCiudad de Buenos AiresArgentina
  5. 5.Unit of Molecular PathologyClinical Research Center (CRC), CeSI, G. d’Annunzio University FoundationChietiItaly
  6. 6.Instituto Alexander FlemingCiudad de Buenos AiresArgentina
  7. 7.Hospital de Niños “Dr. Ricardo Gutierrez”Ciudad de Buenos AiresArgentina

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