There is increasing evidence that high-risk human papilloma virus (HPV) is involved in cancers in addition to cervical cancer. For example, it is generally accepted that HPV has a role in a significant proportion of head and neck tumours, and it has long been hypothesised that hormone dependent oncogenic viruses, such as HPV may have causal roles in some human breast cancers. A number of reports have identified HPV DNA in breast tissue and breast cancer specimens, but these rely on standard polymerase chain reaction (PCR), which is criticised for its propensity for contamination. We have used two different technologies, in situ and standard PCR (with sequencing), and histology based on light microscopy. We unambiguously demonstrate the presence of high-risk HPV in the cells of breast cancer specimens and breast cancer cell lines. In addition, we also show that the oncogenic characteristics of HPV associated breast cancer are very similar to HPV-associated cervical cancer. Specifically, that putative koilocytes are present in some HPV associated breast cancers. The above observations indicate a likely causal role for high-risk HPV in human breast cancer and offer the possibility of primary prevention of some breast cancers by vaccination against HPV.
There are now five studies, including the report of Akil and co-workers in this issue of the Br J Cancer, for which the relationship between age of women and high-risk human papilloma virus (HPV)-positive breast cancer, has been published. Three of these studies report that the age of women with HPV-positive breast cancer is significantly younger than the women with HPV-negative breast cancer. On an average, Greek women with HPV-positive breast cancer were 15 years, Australian women 8 years, and Canadian and Syrian women were 11 years younger than those with HPV-negative breast cancer (Kroupis et al, 2006; Lawson et al, 2006; Akil et al, 2007). Two studies report no difference in the age of women with HPV-positive or -negative breast cancer (Hennig et al, 1999; Damin et al, 2004). Some details of these studies are shown in Table 1.
Table 1
Average age of women with HPV-positive and HPV-negative breast cancer
Based on the younger age of some women with HPV-positive breast cancer, and the higher incidence of HPV-positive cervical cancer among younger women with multiple sexual partners, we have hypothesised that high-risk HPVs may be transmitted to the breast during sexual activities (Lawson et al, 2006).
The underlying assumption to these observations and hypotheses is that high-risk HPVs may have a causal role in some breast cancers. Therefore, a brief overview of the relevant evidence is of value.
The presence of high-risk HPV DNA in breast tumours has been shown, mainly by PCR analyses, in 11 out of 13 studies conducted in a various countries (reviewed by Lawson et al, 2006; plus a recent positive study by Yasmeen et al, 2007; a negative study by Lindel et al, 2007). Tumours of the breast nipple appear to have histological characteristics similar to HPV-positive cervical cancer (de Villiers et al, 2005).
Similar high-risk HPVs have been identified in breast tumours and cervical cancer that have occurred in the same women (Hennig et al, 1999; Widschwendter et al, 2004).
There is immortalisation and preneoplastic transformation of normal breast epithelial cells by HPVs (Band, 1995).
High-risk HPVs, in particular HPV types 16, 18, 31, 33 and less commonly additional types, are the accepted cause of cervical and other ano-genital cancers (IARC, 1995). Less well known is the likely causal role of high-risk HPVs in cancers of the head and neck (van Houten et al, 2001). The biological mechanisms by which HPVs are tropic and oncogenic to epithelial cells is reasonably well known from studies of cervical oncogenesis. These mechanisms include the presence and genomic integration of HPV DNA in epithelial tumours, the expression of the HPV E6 oncogene in the tumour where it binds to and degenerates the tumour suppressor p53 gene allowing unregulated cell proliferation to occur (zur Hausen, 2002). Hormones play a central role on HPV oncogenesis. Estrogens synergise with HPV oncogenes to cause cervical cancer (Brake and Lambert, 2005) and the regulatory region of HPV 16 contains DNA sequences that are responsive to glucocorticoid hormones (Gloss et al, 1987).
Because of the presumably low viral load, PCR analyses for HPV on both formalin-fixed and fresh-frozen breast tumour specimens are difficult and very dependent on the details of the methods used. For example, the negative outcomes by Lindel et al (2007) have probably been because they used the incorrect PCR primers (Damin et al, 2007; Yasmeen et al, 2007). In our own studies, the identification of HPV DNA proved to be difficult and required additional amplification of the DNA before PCR and the use of SYBR Green I to optimise detection (Kan et al, 2005).
The main means of transmission of HPVs appears to be by surface contact. The human papilloma virions are released when the cornified envelope of cells desquamate (Bryan and Brown, 2001). The possibility of transmission of high-risk HPVs during sexual activity is demonstrated by the high prevalence of these viruses in male and female genital organs. The prevalence of high-risk HPVs in male genital organs varies by population and methods of detection. The prevalence of high-risk HPVs in the penile glans, penile shaft, prepuce and scrotum is between 5 and 50%, the perianal area 0–33%, semen 2–83% and urine up to 7% (Dunne et al, 2006). High-risk HPVs are also present in normal, benign hyperplastic and malignant prostate tissues (Zambrano et al, 2002). The prevalence of high-risk HPVs in females varies between populations and dramatically so between age groups, with the prevalence in near normal cervical smears from UK women 61% at ages 20–24 decreasing to 14–15% in those over 50 years (Cotton et al, 2007).
What meaning might be given to these observations? In our view, the evidence that high-risk HPVs may have an aetiological role in human breast cancer is substantial but far from conclusive. Obviously further work needs to be done.
A working hypothesis is that high-risk HPVs may be involved in the initiation of breast cancer among younger women. The Editor now considers correspondence on this publication closed.
It is hypothesised that a combination of childhood and later life infections and excess food consumption, particularly of Western style food, initiates and contributes to atherosclerotic coronary heart disease. To consider this hypothesis we have conducted a brief review of the role of childhood infections, food, and their combined influence on atherosclerosis.
Human papillomaviruses (HPV) may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i) confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii) evidence of HPV infections in benign breast tissues prior to the development of HPV-positive breast cancer in the same patients, (iii) evidence that HPVs are biologically active and not harmless passengers in breast cancer.RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR) analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC).Thirty (3.5%) low-risk and 20 (2.3%) high-risk HPV types were identified in 855 breast cancers from the TCGA database. The high risk types were HPV 18 (48%), HPV 113 (24%), HPV 16 (10%), HPV 52 (10%). Data from the PCR cohort study indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens) followed by HPV 16 (13%). The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens.There were four observations of particular interest: (i) confirmation by both NGS and PCR of the presence of high-risk HPV gene sequences in breast cancers, (ii) a correlation between high-risk HPV in benign breast specimens and subsequent HPV-positive breast cancer in the same patient, (iii) HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of HPV E7 proteins), (iv) HPV oncogenic influences may occur early in the development of breast cancer.
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