The role of cytomegalovirus infection in breast cancer

Field: Medicine (Health Sciences)

Human cytomegalovirus (HCMV) infects 40–70% of the adult population in developed countries, and this rate increases with age. HCMV infection is normally latent with no noticeable symptoms in individuals with a healthy immune system. However, the infection can cause problems in immune-compromised individuals and in the elderly people. Detection rates of >90% have been reported for HCMV DNA and/or proteins in breast tumors, suggesting an association between HCMV infection and breast cancer. However, controversies exist, and it is unclear what role HCMV infection plays in breast cancer. HCMV infection fulfills the criteria of the hallmarks of cancer, including tumor-promoting inflammation. We hypothesized that HCMV infection induces inflammation at the breast tumor site, which promotes breast tumor progression and metastasis. This study reassessed the association between HCMV infection and breast cancer using a collection of 147 breast tumors and ten normal breast adipose tissues from women free of cancer that were obtained from a Canadian patient population. PCR detection methods for HCMV DNA were examined for sensitivity and specificity. Nested PCR targeting for HCMV glycoprotein B (gB) gene was found to be the optimum method of detection. HCMV gB DNA was detected in breast tumors and breast tissues at 40% and 30%, respectively. Although not statistically significant, there was a trend for a higher association of HCMV DNA detection with a negative expression of human epidermal growth factor receptor 2 (HER2) in breast tumors (p=0.06). We also investigated the effects of cytomegalovirus (CMV) infection both in vitro and in vivo. The effects of HCMV challenge on human breast cancer cells and breast tissues were studied in culture, with a focus on viral transcription, replication and cellular expression of inflammatory genes. HCMV did not fully replicate in breast cancer cells, but HCMV immediate early (IE) transcripts and proteins were produced, although in a limited number of cells. Breast cancer cells challenged with HCMV showed increased mRNA expression of inflammatory genes including interleukin (IL)-1β, IL-6, and cyclogoxygenase-2 (COX-2), which could be important in promoting cancer progression. The effects of mouse CMV (mCMV) infection on breast tumor growth and metastasis was investigated in mouse models of breast cancer, including two syngeneic-orthotopic models and one transgenic model with spontaneous breast tumor growth. Prior to breast tumor development, mice were injected with mCMV or negative control medium for 4 days, 11 days or 10 weeks to establish active, intermediate or latent infections, respectively. Infection did not affect tumor growth regardless of these conditions, but latently infected mice showed enhanced development of lung metastases. The breast tumors in latently infected mice also showed worse tumor phenotypes including enhanced vasculature and decreased collagen content, which are features promoting metastasis. Latently infected mice also had increased plasma levels of IL-6 and IL-13, suggesting enhanced inflammation. This work provides insights into the association between CMV infection and breast cancer, with inflammation as an important aspect. These novel results directly linking CMV infection to breast cancer metastasis have important clinical implications since an increased metastasis is prognostic of decreased survival. This work provides evidence that treating or preventing HCMV infections may increase the life expectancy of breast cancer patients by decreasing metastasis.