Influence of the C5a-C5a Receptor System on Breast Cancer Progression and Patient Prognosis

Background: Emerging evidence has shown activation of the complement system in cancer tissues and anaphylatoxin C5a release from C5 by cancer cells, suggesting C5a as a component in the cancer microenvironment. We revealed aberrant expression of C5a receptor (C5aR) in various human cancers and C5a-elicited enhancement of C5aR-expressing cancer cell invasion.

Methods: To explore an influence of the C5a-C5aR system in breast cancer (BC), we investigated BC C5aR expression in relation to clinicopathological parameters of the patients and an effect of C5a on BC cell proliferation.

Results: BC cell C5aR expression was observed immunohistochemically in 22 of 171 patients (13 %) and related to larger tumor size, higher nuclear grade and Ki-67 labeling index, presence of lymph node metastasis and advanced clinical stages. Interestingly, BC cells were C5aR-negative in all patients with BC in situ and C5aR-positive rate was high (38 %) in patients with hormone receptor-negative, namely triple-negative BC. For BC cells in metastasized lymph nodes, 12 of 22 patients (55 %) were C5aR-positive and included 7 patients with C5aR-negative BC in the primary site. Survival rate of patients with C5aR-positive BC was lower than that of patients with C5aR-negative BC. C5a enhanced proliferation of C5aR-expressing triple-negative BC cells in a C5aR-dependent manner.

Conclusion: Relation of BC C5aR expression to tumor development and poor prognosis of the patients and proliferation enhancing effect of C5a on C5aR-expressing BC cells suggest that the C5a-C5aR system is closely associated with BC progression. This system may be a new target to treat BC patients, particularly with triple-negative BC.