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I - Breast cancer risk factors

11. Breast cancer initiating factors: Virus proteins

Not long ago, a mention of the possible causal link between cancer and viral activity would be met with plain dismissal or even ridicule by the majority in professional medicine. But growing evidence can't be denied. At present, viruses are accepted by the official medicine as the cause of a number of cancers: cervix, liver, head, neck, some lymphomas, and others. The International Agency for Research on Cancer (IARC) estimates that 18-20% of all cancers are caused by biological carcinogens.

If something - a virus - resides within the cell, and has a habit of altering cell's DNA, it could be a factor in the malignant cell transformation. Doesn't seem too illogical, does it?

For well over half a century, since it's been found that virus causes breast cancer in mice (Bittner, 1936), it was suspected that it could be causative factor in at least some breast cancers in humans as well. Relatively limited research, however, coupled with limitations in designing, controlling and executing adequate studies, due to the complexity and poor understanding of the disease, failed to produce conclusive results.

How does a virus transform the cell from normal to cancerous? In general, once it infiltrates the cell,

it may be capable of integrating its proteins (i.e. its genetic material, so called tumor proteins) into the cell's DNA

either directly (so called DNA tumor viruses), or, once in the cell, after producing their DNA from their RNA with which they came in (RNA tumor viruses, or retroviruses). Integrating their DNA sequence into cell's DNA, they alter its expression, so that it produces proteins from which new copies of the virus are continuously assembled. Unopposed proliferation of viruses within the cell can ultimately cause its destruction from within.

    Alternately, viral presence and activity can alter cell cycle, possibly pushing it toward malignant transformation.

    If virus proteins stimulate oncogenic activity and/or inhibit activity of tumor-suppressor genes, the infected cell starts proliferating at an accelerated rate. Since part of the tumor-suppressor genes' activity is programmed death (apoptosis) of the cells turning abnormal, such cell can become "immortal" - and start spreading into malignant growth.

For instance, in hepatocellular carcinoma that stems from hepatitis C, human papilloma virus infecting a liver cell produces protein (oncoprotein E6) that binds to the cell's p53 tumor-suppressor protein, making it target of destruction by body's own enzyme.

More recent development in the sophisticated experimental techniques has lead to more suggestive evidence that certain viruses may be among causative and/or promoting factors in the development of breast cancer. Specifically, these are the main candidates:

1. Human papilloma virus (HPV) is a major causative factor in all cervical cancers. It is found more often in the cancerous breast tissue than in the healthy tissue, although data sources vary significantly in that respect, mainly with the country/region (from 4.4% in Mexico, to 86% in the breast cancer tissue in American women). Main difficulty are reliability of detection techniques and/or sample purity. Part of it is also that the viral load in breast cancer seems to be very small: an estimate puts it at 4000 times less than in cervical cancer (for HPV infected Japanese women, Kahn et al. 2008).

HPV viral proteins can inactivate cell's tumor suppressor proteins p53 and pRb; another possible oncogenic mechanism is through elevating levels of c-MYC protein, which stimulates telomere synthesis, making the cell immortal. The latent virus may be activated by elevated ovarian hormones level (e.g. menarche, pregnancy/lactation). HPV may be associated with some invasive/metastatic breast cancer stages; it is is more frequent at a younger age of diagnosis.

When both, cervical and breast cancer are present at the same time, they are infected by HPV of the same type. Breast tissue adjacent to HPV-infected tumor is not infected.

HPV was thought to be transmitted mainly through sexual intercourse (estimated 80% of sexually active adults are infected with at least one type, with HPV 16, 18 and 33 being most carcinogenic, causing about 70% of cervical cancers), but recent evidence suggests that it also occurs through non-sexual forms of physical contact. It could be even possible to transmit the virus by hand.

2. Human mammary tumor virus (HMTV), is nearly identical to the virus causing breast cancer in mice (MMTV), one of the first mammalian viruses for which cancer-causing ability was established. Infecting mostly lymphocytes and mammary epithelial cells, it is found much more frequently in human breast cancers tissues - in about 40% of non-invasive cases, and 72% of invasive cases in U.S. - than in healthy breast tissue (1-2%). HMTV infection is more frequent at a younger age of diagnosis, and with more invasive breast cancer forms.

It was recently classified as human mammary tumor virus, or HMTV (Pogo et al. 2010).

In animal studies, breast cancer aggressiveness is positively correlated with the level of MMTV infection. Similarly to HPV, ovarian hormones stimulate HMTV replication. Long time prevailing objection to HTMV as a causal breast cancer factor was that MMTV is not "compatible" with human cells. However, it is been found that this virus form can not only infect human cells, but can also efficiently replicate inside them (Indik et al. 2005, 2007). No specific mechanism of malignant transformation is definitely established, but several are indicated as possible, one of them being the recent finding of ITAM (immuno-tyrosine
based activation motif)-mediated signaling (Katz et al. 2010).

The virus uses lymphocytes to move around, thus suppression of this immune system activity - which generally results from suppression of the immune system as a whole - can actually be protective: it's been reported that the breast cancer rate in immunosuppressed women due to organ transplant is half the expected rate (Stewart et al. 1995).

Breast cancer tissues in countries with low breast cancer rate - Japan, China - are in much lower proportion infected by HTMV. Coincidently or not, breast cancer rate is also correlated with the regional spread of Mus domesticus (house mice) species, which is considered to be the most MMTV-virulent (Stewart et al. 2000). The virus could be transmitted to humans from mouse deposits (one possible carrier being house cats). It can also be passed through human milk.

3. Human cytomegalovirus (HCMV) is herpesvirus specie linked to a number of cancers (malignant glioma, prostate, skin, colorectal...). In addition to saliva, urine, cervical secretions, and semen, it is often transmitted through breast milk, indicating breast epithelium as a common site of infection. Frequency of infection ranges between 50% and near 100%, but it is always over 90% in cancer cells of malignancies it is associated with (97% in breast cancer tissue, Harkins et al. 2010).

When present in the malignant tissue, the virus is usually not found in the adjacent normal tissues. It is suspected that it increases malignancy of cancer cells, i.e. acts as its promoting factor.

HCMV activity can be part of malignant transformation in a number of ways: by interfering with cell cycle regulation, inhibiting apoptosis, activating angiogenesis and metastatic phenotype, and causing increased mutation rate (Dziurzynski et al. 2012). It also can aid tumor cells in becoming "invisible" to the immune system.

A study of young women found higher HCMV activity in those with breast cancer indicating, if resulting from recently acquired infection, that late  (adult vs. child) exposure to HCMV could carry higher risk (Richardson et al. 2004).

4. Epstein-Barr virus (EBV) infects nearly all world's adult population. It is commonly transmited trough saliva. Most people tolerate infection without symptoms, but EBV is far from harmless. It was linked as a probable co-factor to Burkitt's and Hodgkin's lymphomas, AIDS, as well as in epithelial cell cancers, like nasopharyngeal carcinoma, lymphoepithelioma-like squamous cell malignancies; gastric adenocarcinoma; and leiomyo-sarcoma. It is classified as class I carcinogen by IARC.

Evidence of its active role in breast cancer is, again, contradicting. Studies using methods based on polymerase chain reaction (PCR, 18 studies) did find its association with breast cancer, while those looking for EBV encoded RNA in situ hybridization (EBER-ISH, 5 studies) initially did not (even when PCR  simultaneously would), then one found EBV presence in 49% of cancers, but localized to lymphocytes in the tumor environment, not the tumor cells themselves (Khan et al. 2011). Last scenario, of course, does not exclude the possibility that EBV is actively involved in tumor growth by affecting its environment.

Studies that do find it significantly associated with breast cancer found it in approximately 20-50% of the cases. But its activity and distribution varies, suggesting that from one case to another, it may play either a causal or accessory role - or no active role.

Breast epithelial cells can be infected by EBV from lymphatic cells carrying the virus. EBV-infected breast cancer cells show greater resistance to chemotherapy drugs (Lin et al. 2007).

5. Bovine leukemia virus (BLV) is another possible viral factor in breast cancer. This leukemia virus is common in cattle - approx. 30-40%, with only about 5% of them developing leukemia or lymphoma - and could be transmitted to humans through non-pasteurized milk and undercooked beef. BLV is not limited to blood cells, or cattle. It infects mammary epithelial cells of cows naturally, and other species' cells (including humans and other primates) experimentally.

A study of San Francisco Bay area found 39% frequency of BLV antibodies in the adult female population (Buehring et al. 2003), and another found significantly higher rate of it in women with breast cancer (59% vs. 29% with women not diagnosed with breast cancer, 219 subjects, Buehring et al. 2007). The form of cancer most often associated with BLV infection was ductal carcinoma.

More recent study on half as many subjects did not find a higher rate of infection among women with breast cancer (36% vs. 42% breast cancer and control tissue samples, respectively), but all of the infected samples in control tissues were associated with some form of non-malignant at that point, yet abnormal growth (mainly fibroadenoma, Mesa et al. 2013).

There is no determined specific mechanism through which BLV becomes cancer inducing factor in cattle, and it is still speculative how it could be a part of malignant transformation in human breast cancer. However, the possibility of its active role cannot be ruled out.

6. Human herpesvirus-8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, has been detected in breast cancer in several recent studies. Tsai et al. (2005) see it as a virus the most significantly associated with breast cancer, although it is unclear whether it is only in the context of those investigated by their group. According to them, HHV-8 and HCMV are (so far) the only two viruses whose absence or presence is closely related to relapse-free and overall survival in breast cancer patients.

HHV-8 infects an estimated 1-5% of the U.S. general population. It is probably most often transmitted via saliva (non-sexual), although other routes (sexual, blood transfusion, transplants) also exist.

While HHV-8 malignant potential is certain, possible mechanisms of its action in breast cancer are not determined. If preliminary data by Hsu et al. (2010) of elevated levels of interlukin-6 - cancer related cytokine (signaling protein molecule) - in breast cancer are correct, that could indicate one such mechanism, since HHV-8 is linked to a number of malignancies thought to be driven by cytokines, and particularly IL-6.

7. Herpes simplex virus (HSV) is usually acquired orally in childhood (HSV-1, causing cold sores) or sexually transmitted (HSV-2, genital herpes). It can be also transmitted by contact, direct or indirect, off the infected skin area. Most Americans are infected by HSV-1, and 20-30% by HSV-2.

Specially prepared HSV has cytocidal (cell-killing) potential, and it was actually used in experimental attempts to kill breast cancer cells. The virus is associated with fybroadenoma, the most common form of benign breast tumor, which slightly increases breast cancer risk.

8. Simian virus 40 (SV40) was introduced into humans back in the 1950s through polio-vaccines using virus-contaminated monkey cell cultures. It infects about one third of the U.S. population.

In rodents' models of human breast cancer SV40 antigen expression in mammary epithelium resulted in the formation of precancerous lesions progressing to invasive and metastatic cancers (Marcotte and Muller, 2008, Hoenerhoff et al.2011).

A normal human mammary epithelial cell can be immortalized by SV40 activity.

9. John Cunningham virus (JCV) is another polyomavirus family type. About three in four Americans are infected. Normally, JCV is latent, but can become active if the immune system is suppressed, either due to disease or medication. It was reported detected in 23% of breast carcinoma tissues by Hachana et al. 2012, but not in Antonsson et al. 2012 (the virus normally does not reside in the breast tissue).

It can affect cellular homeostasis through multiple mechanisms, including interfering with p53 tumor-suppressor gene, causing chromosomal instability and cell cycle arrest.

10. Human endogenous retrovirus (HERV) originates from exogenous viruses that infected humans millions years ago and achieved stable (i.e. without causing adverse effects) integration into the human genome (in fact, nearly half of the human genome is of viral origin, and nearly one fifth of it originates from HERV family). It is similar to HTMV, to the extent that the two were hard to separate in the past. Most of the older HERV varieties (the oldest may date 10-20 million years back) have generally become inactive, but the more recent ones, like HERV-K families - which integrated into the human genome some 3-6 million years ago - are still a complete, biologically active virus.

Some HERVs preserved as harmless, hard-to-get-rid of intruders, but others probably benefit the host. For instance, HERV-R apparently plays important role in the immunosuppressive mechanism protecting placenta and embryo from being attacked by the immune system. HERV-W may be aiding in placental morphogenesis. Some HERVs may have protective role against infections by other viruses, or enhancing genome plasticity (quick rearrangements of DNA sequences to maintain or support DNA function).

Of course, anything that has the power to produce a beneficial effect, also has the power to do the opposite.

Normally, HERV-K maintains low activity, but under certain conditions it becomes overactive, and its genes produce viral antigens - functional protein molecules carried on the virus' shell - which can alter cellular environment and become a part of malignant (or other adverse) cellular transformation. HERV-K stimuli can be exogenous (e.g. some chemicals and UV radiation) or endogenous (cytokines, hormones). Overactive production of HERV-K viral antigens is how HERV-K overexpression is detected and measured. It is found in most human breast cancers, but not in healthy breast tissues.

Unlike most other viruses, HERV is not infectious. It is only transmitted vertically, via genome.

Numerous studies have found evidence of the HERV involvement in various cancer forms. It takes place through the expression (production) of messenger RNAs, other active protein forms, and/or retroviral particles. These viral products can negatively affect cellular homeostasis, become productively integrated in cancerous cells' genomes, activate proto-oncogens or promote cancerous growth in other ways, or inhibit immune response.

A specific human mammary carcinoma cell line (T47D) produces retroviral particles, indicating functional presence of HERV genome sequences in the cell line. The production is stimulated by steroid hormones. HERV-K-T47D overexpression significantly correlates with poor prognosis for disease-free and overall survival of breast cancer patients (Golan et al. 2008).

Targeting human breast cancer with anti-HERV-K monoclonal antibodies (2 in 3 cancers had HERV-K env protein overexpression), resulted in significant tumor growth reduction from re-activating the signaling pathway of the tumor-suppressor protein TP53 (Wang-Johanning et al. 2012). In the study, HERV-K positive tumors had nearly doubled the rate of lymph note metastasis than HERV-K negative tumors (43% vs. 23%).

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At this point, we don't know for sure how - or, even if - viral activity becomes important, or key factor in initiating and/or promoting breast cancer. But we do know that it is positively associated with malignant growth in a number of other cancer forms. The evidence we have is very suggestive of the conclusion that it can be a significant factor in some - possibly significant portion - of breast cancers as well.

According to Lawson and Heng (Viruses and breast cancer, 2010), the evidence of viral presence in some breast cancers is conclusive, and that of causative role in breast cancer is suggestive, or very suggestive for both, HPV and MMTV. The evidence of causal relation, or even significant presence, is still inconclusive for the other two, but the possibility that they may have active role in some breast cancers cannot be ruled out.

Other authors would, perhaps, have different views with respect to which viruses are most firmly linked to breast cancers, but the majority consider viral activity to be the likely causative/promoting breast cancer factor.

Next, more on breast cancer promoting factors.

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