• CXCL12
• CCR5Δ32
• CCR2
• cancer
• polymorphisms
• chemokines
• breast
• bladder
• skin
• SDF-1

The molecular biology of cancer is still far from being understood, with the exception of specific familial cases. Amplifications of oncogenes and alterations in tumour suppressor and detoxification genes by mutations or deletions appear especially important in the development of sporadic breast tumours.^1–3

Tumour infiltrating lymphocytes (TILs) and tumour associated macrophages are thought to play a crucial role in tumour immune surveillance and possibly development. The activation and recruitment of lymphocytes is regulated by chemotactic and proinflammatory chemokines such as RANTES (CCL5), MCP-1, and to a lesser extent MIP-1 alpha, MIP-1 beta, and IL-8.^4–7 It has been suggested that melanoma cells evade immune surveillance through the induction of TIL cell death by SDF-1 alpha (CXCL12) and RANTES.⁸ MCP-1 is the natural ligand of the CCR2 chemokine receptor, expressed mainly in the monocytes, activated T lymphocytes, and memory cells,⁹ whereas RANTES is the ligand of CCR5.¹⁰

The relevance of chemokines to malignancy extends beyond leucocyte recruitment. Animal models have shown that chemokine secretion by tumour cells can influence angiogenesis and tumour growth. Expression of angiogenic CXC chemokines by tumour cells in severe combined immunodeficient (SCID) syngenic mice has been shown to enhance tumour growth.¹¹ However, the association of any kind of cancer with chemokine related genetic markers has not been examined to date.

We selected the polymorphisms CCR2–64I,¹² CXCL12–3′A, CCR5Δ32, and CCR5 59029 G-A^10,13 because of functional and clinical data from AIDS studies. We determined the genotype for the above four polymorphisms in 442 cancer samples and 361 control samples. Our data indicate a significant involvement of the chemokine system in the development of breast cancer.