Human papillomavirus E6 alters Toll-like receptor 9 transcripts and chemotherapy responses in breast cancer cells in vitro

Abstract

Background: Toll-like receptor 9 (TLR9) is a DNA recognizing receptor expressed also in several cancers. Decreased TLR9 expression is associated with poor prognosis in triple negative breast cancer (TNBC), but the role of TLR9 in breast cancer pathophysiology is currently unclear. Regulation of TLR9 expression in breast cancer is poorly understood. Human papillomavirus (HPV) infections suppress TLR9 expression in cervical cancers but the association between HPV and breast cancer has remained controversial. The aim of this study was to test if HPV16 can suppress TLR9 expression in breast cancer cells and affect cell behavior. Methods and results: Human T-47D and MDA-MB-231 breast cancer cells were transduced with lentivirus encoding HPV16 E6 oncoprotein. The effects of E6 on TLR9 mRNA and protein expression, and cell proliferation, migration, invasion and sensitivity to chemotherapy were studied in vitro. Breast cancer tissue samples (n = 37) were analyzed for the presence of HPV DNA. E6 expression decreased TLR9 mRNA expression in MDA-MB-231 and T-47D cells in hypoxia. E6 expression altered breast cancer cell proliferation and made cells significantly less sensitive to the growth inhibitory effects of chemotherapeutic agents. HPV L1 gene was not detected in a small pilot cohort of clinical breast cancer specimens. Conclusion: HPV16 may influence breast cancer cell TLR9 transcription and chemotherapy responses and could thereby affect breast cancer prognosis. These results suggest that HPV may have a previously unrecognized role in breast cancer pathophysiology and warrant further studies on the topic.