Abstract:
Inflammatory breast cancer (IBC) is a highly aggressive phenotype of breast cancer that is
characterized by a high incidence early metastasis. We previously reported a significant
association of human cytomegalovirus (HCMV) DNA in the carcinoma tissues of IBC
patients but not in the adjacent normal tissues. HCMV-infected macrophages serve as
“mobile vectors” for spreading and disseminating virus to different organs, and IBC cancer
tissues are highly infiltrated by tumor-associated macrophages (TAMs) that enhance IBC
progression and promote breast cancer stem cell (BCSC)-like properties. Therefore, there
is a need to understand the role of HCMV-infected TAMs in IBC progression. The present
study aimed to test the effect of the secretome (cytokines and secreted factors) of TAMs
derived from HCMV+ monocytes isolated from IBC specimens on the proliferation,
invasion, and BCSC abundance when tested on the IBC cell line SUM149. HCMV+
monocytes were isolated from IBC patients during modified radical mastectomy surgery
and tested in vitro for polarization into TAMs using the secretome of SUM149 cells. MTT,
clonogenic, invasion, real-time PCR arrays, PathScan Intracellular Signaling array, and
cytokine arrays were used to characterize the secretome of HCMV+ TAMs for their effect
on the progression of SUM149 cells. The results showed that the secretome of HCMV+
TAMs expressed high levels of IL-6, IL-8, and MCP-1 cytokines compared to HCMV-
TAMs. In addition, the secretome of HCMV+ TAMs induced the proliferation, invasion,
colony formation, and expression of BCSC-related genes in SUM149 cells compared to
mock untreated cells. In addition, the secretome of HCMV+ TAMs activated the
phosphorylation of intracellular signaling molecules p-STAT3, p-AMPKa, p-PRAS40,
and p-SAPK/JNK in SUM149 cells. In conclusion, this study shows that the secretome
of HCMV+ TAMs enhances the proliferation, invasion, colony formation, and BCSC properties by activating the phosphorylation of p-STAT3, p-AMPKa, p-PRAS40, and p-
SAPK/JNK intracellular signaling molecules in IBC cells.
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