Invited Brief Commentary on the Article “Breast Cancer Association with Cytomegalo Virus - a Tertiary Center Case-Control Study” Is Cytomegalo Virus a Breast Cancer Etiologic Risk Factor?

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Breast Cancer Association with Cytomegalo Virus—A Tertiary Center Case-Control Study

Carcinogenesis is a complex process, which is affected by a wide variety of factors. Despite enormous progress in medical sciences in recent years, the etiology of many cancer diseases has not been thoroughly studied. Apart from chemical, physical, biological and genetic makeup, the role of infectious factors has been increasingly frequently emphasized. Infectious factors, including viruses as the most frequent underlying cause, have been estimated to contribute to about 15–20% of cancers.¹ When the participation of the infectious factor is considered in the development of neoplasms, treatment possibilities and prevention of the development of this process can be increased. In this context, studies to confirm or exclude the contribution of the infectious factor are of particular importance.

The cytomegalovirus (CMV) association with breast cancer has caused much controversy and some uncertainty. Cytomegalovirus is widespread in the world in a slightly different way in different populations. It is estimated that infection with this virus is from 40% to 80% of the population in developed countries and almost 100% in developing countries. The CMV seroprevalence is dependent on the underlying demographic characteristics and on socioeconomic status and geographical conditions.² CMV is transmitted through the droplet route of infection, during prenatal period and delivery, through transfused blood and with sperm, vaginal discharge, urine and milk produced by mammary glands. Ease of transmission and latent nature of CMV infections are additional indications for studies in oncogenetic mechanisms of this virus in the aspects of epidemiology and public health. Knowledge of the importance of CMV in breast cancer etiopathogenesis is not only of cognitive value, but also of important practical implications. Possible confirmation of the etiopathogenic link between CMV infection and breast cancer creates an opportunity to implement CMV infection prevention measures and develop a new paradigm of breast cancer treatment. Viruses associated with human cancer may induce neoplastic changes in varied ways. The main mechanisms of cancer development include insertion mutagenesis and oncogene transduction. In the former case, the virus integrates with the host's genome in the vicinity of protooncogenes, while in the case of oncogene transduction, the virus itself is an oncogene carrier. However, the virus is considered as an etiologic risk factor for cancer only if it meets all three basic requirements. There must be an epidemiological link between the occurrence of cancer and the virus; viral material (antigen or genome) is found in tumor cells; the virus should be isolated from the tumor tissue and be capable of in vitro cell transformation.

To date, there is no clear evidence of direct involvement of CMV in the ontogenesis of breast cancer. Some researchers^3,4 could not support the finding that CMV infection can be correlated with breast cancer progression by comparing malignant and non-malignant tumors tissues using real-time PCR. Surendran and Chisthi⁵ compared the antibody titers against CMV among benign and malignant breast cancer cases and they did not find a link between CMV and breast cancer. The authors approached their research with due diligence and in the manuscript they highlighted the limitations of their study. Serological tests used by Surendran and Chisthi³ are indirect methods of diagnosing CMV infection and do not always have a full diagnostic value. The levels of antibody titres for IgG and IgM did not allow unequivocal conclusions to be drawn. IgM antibodies can persist in blood serum for several months after infection, but their presence may also result from the reactivation of latent infection. In turn, the plateau of IgG antibody levels is individually variable; there are also large differences in the results obtained, depending on the test method used. The variety of the serological responses often require verification using molecular methods which also have some limitations and are sometimes unable to confirm the association of CMV with breast cancer.

On the other hand, several investigations suggest the involvement of CMV in various malignancies including breast cancer. CMV antigens and DNA have been detected in tissue biopsies of breast cancers. However, it must be remembered that the finding of CMV in tumor tissues does not provide clear evidence for the involvement of the virus in carcinogenesis. However, the presence of CMV in the primary breast tumor as well as its metastases, while adjacent healthy tissues remained CMV negative, may provide arguments indicating that cytomegalovirus is associated with the etiopathogenesis of breast cancer.⁶ Recently conducted large-scale studies determined that the levels of antibodies to the CMV glycoprotein B are different between patients with breast cancer and matched controls.⁷ These studies can suggest a link between CMV and breast cancer. The above evidence of CMV's role in breast cancer etiology is inconclusive.

Further studies on the confirmation or exclusion of CMV association with breast cancer may be important considering the reports on carcinomas other than breast cancer which suggest an increase in the aggressiveness of tumor under the influence of CMV.⁸ There are also studies on a murine model of human hepatocellular carcinoma which, in turn, report on the regression of tumors upon infections of CMV.⁹ It is still not clear why CMV cannot replicate in all cancerous cells.¹⁰ These and other issues related to CMV association with various malignancies including breast cancer require further study. Since CMV infections and breast cancer are serious public health problems, studies of the potential role of CMV in the initiation and progression of breast cancer are extremely important. It is hoped that the controversial findings concerning the relationship between CMV and breast cancer development, in studies conducted in different countries, will inspire other investigators to continue studies in this area.

DECLARATION OF INTEREST

The author declares that no conflict of interest exists. The author declares that she has no competing interests.

The author alone is responsible for the content and writing of the paper.

The author declares that this commentary has not been published elsewhere and that it has not been submitted simultaneously for publication elsewhere.

Additional information

Funding

University of Warmia and Mazury in Olsztyn Faculty of Health Sciences (Grant number 62.610.001-300)