The complement receptors C3aR and C5aR1 have been implicated for roles in tumourigenesis in numerous murine cancer models. However the few studies investigating the role of these proteins in breast cancer have produced conflicting results. Thus we sought to clarify the role of C3a and C5a in murine syngeneic breast cancer models, EMT6 and 4T1.
In accord with previous studies, we found that primary mammary tumour growth was inhibited by daily treatment of mice with the C3aR antagonist SB290157, whereas the C5aR1 antagonist PMX53 had no effect. However treatment with a dual C3aR/C5aR1 agonist (YSFKPMPLaR; EP54) significantly slowed mammary tumour development and progression, suggesting that complement receptor activation, in particular C5aR1, may protect against mammary tumour growth.
Examination of receptor expression by qPCR analysis showed very low levels of mRNA expression for either C3aR or C5aR1 by EMT6 or 4T1 mammary carcinoma cell lines compared with the J774 macrophage line or bone marrow-derived macrophages. Moreover, flow cytometric analysis found no evidence of C3aR or C5aR1 protein expression by either EMT6 or 4T1 cells, leading us to hypothesize that the tumour inhibitory effects of EP54 are indirect, possibly via regulation of the anti-tumour immune response. This hypothesis was supported by flow cytometric analysis which demonstrated a significant increase in tumour infiltrating T lymphocytes in EP54-treated mice.
In summary, these results support an immunoregulatory role for complement receptors in primary murine mammary carcinoma models. They also suggest that complement activation peptides can influence the anti-tumour response in different ways, depending on the tumour type and the host immune response within the tumour microenvironment.