Background: Although the association of human papillomavirus (HPV) with many cancers is well established, the involvement of HPV in breast cancer remains controversial. The purpose of this study is to perform a comprehensive review of the results and methods used to demonstrate that HPV markers are present in human breast cancer, and how well these studies fulfil the criteria for proving the viral etiology of a cancer. Study Design: We conducted a search for molecular studies published until November 2016 that relate human breast cancer to HPV. Results: Forty-three original molecular studies were found, some of which compared cases to nonneoplastic controls. Some investigations did not identify HPV in mammary tissue, but others identified it with different frequencies of positivity, varying between 1.2 and 86%. In most case-control studies (21/24 studies), positivity in cases was found to be higher than in controls, but odds ratios and confidence intervals were not reported. Conclusion: The results are controversial. However, they arouse a great interest in the potential participation of HPV in breast carcinogenesis, but rather as an essential cause-effect participant, at least as a co-participant in some cases. The circumstance of HPV positivity in breast cancer can be criticized, but the elements that clearly demonstrate it in a number of cases are also relevant.

Siegel R, Miller K, Jemal A: Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5–29.
Instituto Nacional de Câncer José Alencar Gomes da Silva:
Dumitrescu R, Cotarla I: Understanding breast cancer risk – where do we stand in 2005? J Cell Mol Med 2015; 9: 208–221.
Hortobagyi G, De la Garza Salazar J, Pritchard K, Amadori D, Haidinger R, Hudis CA, Khaled H, Liu MC, Martin M, Namer M, O’Shaughnessy JA, Shen ZZ, Albain KS; ABREAST Investigators: The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer 2005; 6: 391–401.
Bittner JJ: Possible relationship of the oestrogenic hormones, genetic susceptibility and milk influence in the production of mammary cancer in mice. Cancer Res 1943; 2: 710–721.
Henle G, Henle WJ: Immunofluorescence in cells derived from Burkitt’s lymphoma. J Bacteriol 1966; 91: 1248–1256.
Moore PS, Chang Y: Why do viruses cause cancer? Highlights of the first century of human tumor virology. Nat Rev Cancer 2010; 10: 878–889.
Moore DH, Charney J, Kramarsky B, Lasfragues EY, Sarkar NH, Brennan MJ, Burrows JH, Sirsat SM, Paymaster JC, Vaidya AB: Search for a human breast cancer virus. Nature 1971; 229: 611–615.
Chattopadhyay J, Chattopadhyay U, Chowdhury JR: Immunological relatedness of murine mammary tumor associated antigen and human breast cancer. Gan 1984; 75: 342–348.
Litvinov SV, Golovkina TV, Kriukova IN, Vasilevskaia LN: A protein related to the main core protein of the mouse mammary cancer virus in a microparticle fraction of human milk (article in Russian). Biull Eksp Biol Med 1987; 103: 338–340.
Mesa-Tejada R, Keydar I, Ramanarayanan M, Ohno T, Fenoglio C, Spielgelman S: Detection in human breast carcinomas of an antigen immunologically related to a group-specific antigen of mouse mammary tumor virus. Proc Natl Acad Sci USA 1978; 75: 1529–1533.
Schlom J, Spiegelman S, Moore D: RNA-dependent DNA polymerase activity in virus like particles isolated from human milk. Nature 1971; 231: 97–100.
Axel R, Schlom J, Spiegelman S: Presence in human breast cancer of RNA homologous to mouse mammary tumour virus RNA. Nature 1972; 235: 32–36.
Vaidya AB, Black MM, Dion AS, Moore DH: Homology between human breast tumour RNA and mouse mammary tumour virus genome. Nature 1974; 249: 565–567.
Furmanski P, Longley C, Fouchey D, Rich R, Rich MA: Normal human mammary cells in culture: evidence for oncornavirus like particles. J Natl Cancer Inst 1974; 52: 975–977.
McGrath CM: Replication of mammary tumor virus in tumor cell cultures: dependence on hormone-induced cellular organisation. J Natl Cancer Inst 1971; 47: 455–467.
Keydar I, Ohno T, Nayak R, Sweet R, Simoni F, Weiss F, Karby S, Mesa Tejada R, Spiegelman S: Properties of retrovirus like particles produced by a human breast carcinoma cell line: immunological relationship with mouse mammary tumor virus proteins. Proc Natl Acad Sci USA 1984; 81: 4188–4192.
Mant C, Cason J: A human murine mammary tumour virus-like agent is an unconvincing aetiological agent for human breast cancer. Rev Med Virol 2004; 14: 169–177.
May FE, Westley BR, Rochefort H, Buetti E, Diggelmann H: Mouse mammary tumour virus-related sequences are present in human DNA. Nucleic Acids Res 1983; 11: 4127–4139.
Wang Y, Holland JF, Bleiweiss IJ, Melana S, Liu X, Pelisson I, Cantarella A, Stellrecht K, Mani S, Pogo BG: Detection of mammary tumor virus Env gene-like sequences in human breast cancer. Cancer Res 1995; 55: 5173–5179.
Beaulieu BL, Sullivan JL: Epstein-Barr virus; in Richmann DD, Whitley RJ, Hayden FG (eds): Clinical Virology, ed 2. Washington, ASM Press, 2002, p 483.
Higgins CD, Swerdlow AJ, Macsween KF, Harrison N, Williams H, McAulay K, Thomas R, Reid S, Conacher M, Britton K: A study of risk factors for acquisition of Epstein-Barr virus and its subtypes. J Infect Dis 2007; 195: 474–482.
Labrecque LG, Barnes DM, Fentiman IS, Griffin BE: Epstein-Barr virus in epithelial cell tumors: a breast cancer study. Cancer Res 1995; 55: 39–45.
Sasco AJ, Lowenfels AB, Pasker-de Jong P: Review article: epidemiology of male breast cancer. A meta-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer 1993; 53: 538–549.
Abhyankar SH, Chiang KY, McGuirk JP, Pati AR, Godder KT, Welsh JA, Waldron RL, McElveen JL, Henslee-Downey PJ: Late onset Epstein-Barr virus-associated lymphoproliferative disease after allogeneic bone marrow transplant presenting as breast masses. Bone Marrow Transplant 1998; 21: 295–297.
Lespagnard L, Cochaux P, Larsimont D, Degeyter M, Velu T, Heimann R: Absence of Epstein-Barr virus in medullary carcinoma of the breast as demonstrated by immunophenotyping, in situ hybridization and polymerase chain reaction. Am J Clin Pathol 1995; 103: 449–452.
Bonnez W: Papillomavirus; in Richmann DD, Whitley RJ, Hayden FG (eds): Clinical Virology, ed 2. Washington, ASM Press, 2002, p 583.
Hobbs CGL, Sterne JAC, Bailey M, Heyderman RS, Birchall MA, Thomas SJ: Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol 2006; 31: 259–266.
Band V, Zajchowski D, Kulesa V, Sager R: Human papilloma virus DNAs immortalize normal human mammary epithelial cells and reduce their growth factor requirements. Proc Natl Acad Sci USA 1990; 87: 463–467.
Leminen A, Paavonen J, Vesterinen E, Wahlström T, Rantala I, Lehtinen M: Human papillomavirus types 16 and 18 in adenocarcinoma of the uterine cervix. Am J Clin Pathol 1991; 95: 647–652.
Lawson JS: Do viruses cause breast cancer? Methods Mol Biol 2009; 471: 421–438.
Mant C, Hodgson S, Hobday R, D’Arrigo C, Cason J: A viral aetiology for breast cancer: time to reexamine the postulate. Intervirology 2004; 47: 2–13.
Lawson JS, Gunzburg WH, Whitaker NJ: Viruses and human breast cancer. Future Microbiol 2006; 1: 33–51.
Lawson JS, Tran D, Rawlinson WD: From Bittner to Barr: a viral, diet, and hormone breast cancer aetiology hypothesis. Breast Cancer Res 2001; 3: 81–85.
Hill AB: The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300.
Evans AS, Mueller NE: Viruses and cancer. Causal associations. Ann Epidemiol 1990; 1: 71–92.
Susser M: What is a cause, how do we know one? A grammar for pragmatic epidemiology. Am J Epidemiol 1991; 133: 635–648.
Di Lonardo A, Venuti A, Marcante ML: Human papillomavirus in breast cancer. Breast Cancer Res Treat 1992; 21: 95–100.
Bratthauer GL, Tavassoli FA, O’Leary TJ: Etiology of breast carcinoma: no apparent role for papillomavirus types 6/11/16/18. Pathol Res Pract 1992; 188: 384–386.
Wrede D, Luqmani YA, Coombes RC, Vousden KH: Absence of HPV 16 and 18 DNA in breast cancer. Br J Cancer 1992; 65: 891–894.
Czerwenka K, Heuss F, Hosmann JW, Manavi M, Lu Y, Jelincic D, Kubista E: Human papilloma virus DNA: a factor in the pathogenesis of mammary Paget’s disease? Breast Cancer Res Treat 1996; 41: 51–57.
Gopalkrishna V, Singh UR, Sodhani P, Sharma JK, Hedau ST, Mandal AK, Das BC: Absence of human papillomavirus DNA in breast cancer as revealed by polymerase chain reaction. Breast Cancer Res Treat 1996; 39: 197–202.
Hennig EM, Suo Z, Thoresen S, Holm R, Kvinnsland S, Nesland JM: Human papillomavirus 16 in breast cancer of women treated for high grade cervical intraepithelial neoplasia (CIN III). Breast Cancer Res Treat 1999; 53: 121–135.
Yu Y, Morimoto T, Sasa M, Okazaki K, Harada Y, Fujiwara T, Irie Y, Takahashi E, Tanigami A, Izumi K: HPV33 DNA in premalignant and malignant breast lesions in Chinese and Japanese populations. Anticancer Res 1999; 19: 5057–5061.
Yu Y, Morimoto T, Sasa M, Okazaki K, Harada Y, Fujiwara T, Irie Y, Takahashi E, Tanigami A, Izumi K: Human papillomavirus type 33 DNA in breast cancer (article in Chinese). Breast Cancer 2000; 7: 33–36.
Liu Y, Klimberg VS, Andrews NR, Hicks CR, Peng H, Chiriva-Internati M, Henry-Tillman R, Hermonat PL: Human papillomavirus DNA is present in a subset of unselected breast cancers. J Hum Virol 2001; 4: 329–334.
Li T, Lu ZM, Guo M, Wu QJ, Chen KN, Xing HP, Mei Q, Ke Y: p53 Codon 72 polymorphism (C/G) and the risk of human papillomavirus-associated carcinomas in China. Cancer 2002; 95: 2571–2576.
Damin AP, Karam R, Zettler CG, Caleffi M, Alexandre CO: Evidence for an association of human papillomavirus and breast carcinomas. Breast Cancer Res Treat 2004; 84: 131–137.
Widschwendter A, Brunhuber T, Wiedemair A, Mueller-Holzner E, Marth C: Detection of human papillomavirus DNA in breast cancer of patients with cervical cancer history. J Clin Virol 2004; 31: 292–297.
de Villiers EM, Sandstrom RE, zur Hausen H, Buck CE: Presence of papillomavirus sequences in condylomatous lesions of the mamillae and in invasive carcinoma of the breast. Breast Cancer Res 2005; 7:R1–R11.
Tsai JH, Tsai CH, Cheng MH, Lin SJ, Xu FL, Yang CC: Association of viral factors with non-familial breast cancer in Taiwan by comparison with non-cancerous, fibroadenoma, and thyroid tumor tissues. J Med Virol 2005; 75: 276–281.
Kan CY, Iacopetta BJ, Lawson JS, Whitaker NJ: Identification of human papillomavirus DNA gene sequences in human breast cancer. Br J Cancer 2005; 93: 946–948.
Kroupis C, Markou A, Vourlidis N, Dionyssiou-Asteriou N, Lianidou ES: Presence of high-risk human papillomavirus sequences in breast cancer tissues and association with histopathological characteristics. Clin Biochem 2006; 39: 727–731.
Gumus M, Yumuk PF, Salepci T, Aliustaoglu M, Dane F, Ekenel M, Basaran G, Kaya H, Barisik N, Turhal NS: HPV DNA frequency and subset analysis in human breast cancer patients’ normal and tumoral tissue samples. J Exp Clin Cancer Res 2006; 25: 515–521.
Choi YL, Cho EY, Kim JH, Nam SJ, Oh YL, Song SY, Yang JH, Kim DS: Detection of human papillomavirus DNA by DNA chip in breast carcinomas of Korean women. Tumor Biol 2007; 28: 327–332.
Lindel K, Forster A, Altermatt HJ, Greiner R, Gruber G: Breast cancer and human papillomavirus (HPV) infection: no evidence of a viral etiology in a group of Swiss women. Breast 2007; 16: 172–177.
Akil N, Yasmeen A, Kassab A, Ghabreau L, Darnel AD, Al Moustafa AE: High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: a tissue microarray study. Br J Cancer 2008; 99: 404–407.
de Cremoux P, Thioux M, Lebigot I, Sigal-Zafrani B, Salmon R, Sastre-Garau X: No evidence of human papillomavirus DNA sequences in invasive breast carcinoma. Breast Cancer Res 2008; 109: 55–58.
Khan NA, Castillo A, Koriyama C, Kijima Y, Umekita Y, Ohi Y, Higashi M, Sagara Y, Yoshinaka H, Tsuji T: Human papillomavirus detected in female breast carcinomas in Japan. Br J Cancer 2008; 99: 408–414.
De Leon DC, Montiel DP, Nemcova J, Mykyskova I, Turcios E, Villavicencio V, Cetina L, Coronel A, Hes O: Human papillomavirus (HPV) in breast tumors: prevalence in a group of Mexican patients. BMC Cancer 2009; 9: 26.
He Q, Zhang SQ, Chu YL, Jia XL, Wang XL: The correlations between HPV16 infection and expressions of c-erbB-2 and bcl-2 in breast carcinoma. Mol Biol Rep 2009; 36: 807–812.
Heng B, Glenn WK, Ye Y, Tran B, Delprado W, Lutze-Mann L, Whitaker NJ, Lawson JS: Human papilloma virus is associated with breast cancer. Br J Cancer 2009; 101: 1345–1350.
Mendizabal-Ruiz AP, Morales EJA, Ramirez-Jirano LJ, Padilla-Rosa EM, Moran-Moguel MC, Montoya-Fuentes EH: Low frequency of human papillomavirus DNA in breast cancer tissue. Breast Cancer Res 2009; 114: 189–194.
Hachana M, Ziadi S, Amara K, Toumi I, Korbi S, Trimeche M: No evidence of human papillomavirus DNA in breast carcinoma in Tunisian patients. Breast 2010; 19: 541–544.
Hedau S, Kumar U, Hussain S, Shukla S, Pande S, Jain N: Breast cancer and human papillomavirus infection: no evidence of HPV etiology of breast cancer in Indian women. BMC Cancer 2011; 11: 27–37.
Silva RG, da Silva BB: No evidence for an association of human papillomavirus and breast carcinoma. Breast Cancer Res Treat 2011; 125: 261–264.
Baltzell K, Buehring GC, Krishnamurthy S, Kuerer H, Shen HM, Sison JD: Limited evidence of human papillomavirus in breast tissue using molecular in situ methods. Cancer 2012; 118: 1212–1220.
Mou X, Chen L, Liu F, Shen Y, Wang H, Li Y, Yuan L, Lin J, Lin J, Teng L, Xiang C: Low prevalence of human papillomavirus (HPV) in Chinese patients with breast cancer. J Int Med Res 2011; 39: 1636–1644.
Chang P, Wang T, Yao Q, Lv Y, Zhang J, Guo W: Absence of human papillomavirus in patients with breast cancer in north-west China. Med Oncol 2012; 29: 521–525.
Frega A, Lorenzon L, Bononi M, De Cesare A, Ciardi A, Lombardi D: Evaluation of E6 and E7 mRNA expression in HPV DNA positive breast cancer. Eur J Gynaecol Oncol 2012; 33: 164–167.
Glenn WK, Heng B, Delprado W, Iacopetta B, Whitaker NJ, Lawson JS: Epstein-Barr virus, human papillomavirus and mouse mammary tumour virus as multiple viruses in breast cancer. PLoS One 2012; 7:e48788.
Sigaroodi A, Nadji SA, Naghshvar F, Nategh R, Emami H, Velayati AA: Human papillomavirus is associated with breast cancer in the north part of Iran. ScientificWorldJournal 2012; 2012: 837191.
Liang W, Wang J, Wang C, Lv Y, Gao H, Zhang K: Detection of high-risk human papillomaviruses in fresh breast cancer samples using the hybrid capture 2 assay. J Med Virol 2013; 85: 2087–2092.
Ali SH, Al-Alwan NA, Al-Alwany SH: Detection and genotyping of human papillomavirus in breast cancer tissues from Iraqi patients. East Mediterr J 2014; 20: 372–377.
Ahangar-Oskouee M, Shahmahmoodi S, Jalilvand S, Mahmoodi M, Ziaee AA, Esmaeili HA: No detection of “high-risk” human papillomaviruses in a group of Iranian women with breast cancer. Asian Pac J Cancer Prev 2014; 15: 4061–4065.
Manzouri L, Salehi R, Shariatpanahi S, Rezaie P: Prevalence of human papilloma virus among women with breast cancer since 2005–2009 in Isfahan. Adv Biomed Res 2014; 3: 75.
Peng J, Wang T, Zhu H, Guo J, Li K, Yao Q: Multiplex PCR/mass spectrometry screening of biological carcinogenic agents in human mammary tumors. J Clin Virol 2014; 61: 255–259.
Fu L, Wang D, Shah W, Wang Y, Zhang G, He J: Association of human papillomavirus type 58 with breast cancer in Shaanxi province of China. J Med Virol 2015; 87: 1034–1040.
Vernet-Tomas M, Mena M, Alemany L, Bravo I, De Sanjose S, Nicolau P: Human papillomavirus and breast cancer: no evidence of association in a Spanish set of cases. Anticancer Res 2015; 35: 851–856.
Li J, Ding J, Zhai K: Detection of human papillomavirus DNA in patients with breast tumor in China. PLoS One 2015; 10:e0136050.
Gillio-Tos A, De Marco L, Fiano V, Garcia-Bragado F, Dikshit R, Boffetta P, Merletti F: Efficient DNA extraction from 25-year-old paraffin-embedded tissues: study of 365 samples. Pathology 2007; 39: 345–348.
Morris B: Cervical human papillomavirus screening by PCR: advantages of targeting the E6/E7 region. Clin Chem Lab Med 2005; 43: 1171–1177.
Glaser SL, Hsu JL, Gulley ML: Epstein-Barr virus and breast cancer: state of the evidence for viral carcinogenesis. Cancer Epidemiol Biomarkers Prev 2004; 13: 688–697.
Longworth MS, Laimins LA: Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Molec Biol Rev 2004; 68: 362–372.
Joshi D, Buehring GC: Are viruses associated with human breast cancer? Scrutinizing the molecular evidence. Breast Cancer Res Treat 2012; 135: 1–15.
Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J: Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009; 27: 1992–1998.
Fakhry C, Westra WC, Li S: Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100: 261–269.
Licitra L, Perrone F, Bossi P: High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006; 24: 5630–5636.
Weinberger PM, Yu Z, Haffty BG: Prognostic significance of p16 protein levels in oropharyngeal squamous cell cancer. Clin Cancer Res 2004; 10: 5684– 5691.
Petrelli F, Sarti E, Barni S: Predictive value of human papillomavirus in oropharyngeal carcinoma treated with radiotherapy: an updated systematic review and meta-analysis of 30 trials. Head Neck 2014; 36: 750–759.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.