Abstract

Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.

Highlights

  • Breast cancer (BC) is the most common cancer in women worldwide

  • Lytic human cytomegalovirus (HCMV) infection leads to a dysregulated cell cycle, and the immediate early (IE) gene products interfere with key cellular factors, including retinoblastoma protein family (Rb), cyclins, p53, Wnt, phosphatidylinositol 3-kinase/Akt, human telomerase reverse transcriptase, and NF-κB to increase the immortal properties of infected cells [11]

  • Especially triple-negative BC (TNBC), the tumor cells frequently express several HCMV gene products, which may be a result of an oncogenic infection in breast epithelial cells

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Summary

A Review of the Potential Role of Human

Jürgen Geisler 1,2 , Joel Touma 1,2,3 , Afsar Rahbar 4,5 , Cecilia Söderberg-Nauclér 4,5 and. Received: 25 October 2019; Accepted: 19 November 2019; Published: 22 November 2019

Background
Oncogenic Properties of HCMV
HCMV in Breast Cancer
The HCMV Signature in Transformed Breast Epithelial Cells
Relevance of HCMV in the BC Microenvironment
Findings
Conclusions
Full Text
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