PDGFRα Enhanced Infection of Breast Cancer Cells with Human Cytomegalovirus but Infection of Fibroblasts Increased Prometastatic Inflammation Involving Lysophosphatidate Signaling

Abstract

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. HCMV proteins and DNA are detected in tumors and metastases, suggesting an association with increased invasion. We investigated HCMV infection in human breast cancer cell lines compared to fibroblasts, a component of tumors, and the role of platelet-derived growth factor receptor-α (PDGFRα). HCMV productively infected HEL299 fibroblasts and, to a lesser extent, Hs578T breast cancer cells. Infection of another triple-negative cell line, MDA-MB-231, and also MCF-7 cells, was extremely low. These disparate infection rates correlated with expression of PDGFRA, which facilitates HCMV uptake. Increasing PDGFRA expression in T-47D breast cancer and BCPAP thyroid cancer cells markedly increased HCMV infection. Conversely, HCMV infection decreased PDGFRA expression, potentially attenuating signaling through this receptor. HCMV infection of fibroblasts promoted the secretion of proinflammatory factors, whereas an overall decreased secretion of inflammatory factors was observed in infected Hs578T cells. We conclude that HCMV infection in tumors will preferentially target tumor-associated fibroblasts and breast cancer cells expressing PDGFRα. HCMV infection in the tumor microenvironment, rather than cancer cells, will increase the inflammatory milieu that could enhance metastasis involving lysophosphatidate.

Human Cytomegalovirus Seropositivity and Viral DNA in Breast Tumors Are Associated with Poor Patient Prognosis

“…In experiments with cultured cells, we showed that the level of HCMV infectivity of different breast cancer cell lines was much lower than in fibroblasts. This did not depend on whether the breast cancer cells were triple negative or hormone receptor positive [ 59 ]. Instead, infection levels depended on the expression of PDGFRα.…”

“…Alternatively, these discrepancies in the detection of HCMV in breast tumors could also be due to variability in the cellular composition of the breast tumors. We recently showed that the incidence of HCMV infection of breast cancer cells is considerably less than that of fibroblasts with higher infection dependent on the expression of platelet-derived growth factor receptor alpha (PDGFRα) [ 59 ]. Fibroblasts are a component of the microenvironment and they are likely to be infected more than the breast cancer cells.…”

The assembled and annotated genome of the masked palm civet (Paguma larvata)

“…One of known human viral receptor genes, PDGFRA , was included in genes under positive selection in P. larvata. PDGFRA can activate mutations in gastrointestinal stromal tumors [ 68 ] and is required for human cytomegalovirus infection [ 69 , 70 ]. There has been no study focus on the PDGFRA receptor in masked palm civets, and further study is needed.…”

Innate Immune Program in Formation of Tumor-Initiating Cells from Cells-of-Origin of Breast, Prostate, and Ovarian Cancers

“…In addition to bacteria, there is also evidence showing a potential relationship of viral infection with breast cancer. Infection with human cytomegalovirus (CMV) is common in adults in developed countries (~40-70%), and this virus was shown to preferentially infect breast cancer cells with elevated expression of platelet-derived growth factor receptorα (PDGFRα) and fibroblasts (which have high levels of PDGFRα expression); infection of PDGFRα + fibroblasts raised the possibility that human CMV infection could affect the tumor microenvironment, leading to a more inflammatory milieu [110]. Previous research also reported some conflicting data of the potential roles of HPV, EBV, or MMTV in breast cancer, but the precise roles of these viruses in breast tumorigenesis remain unclear [111,112].…”