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Background  The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 ( Sipa1 ) underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing  Sipa1  cell line developing 1.5 to 2 fold more surface pulmonary metastases.  Sipa1  encodes a mitogen-inducible GTPase activating (GAP) protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline  SIPA1  SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that  SIPA1  may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of  SIPA1  and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia.    Methods  The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program.    Results  Results indicated significance with  SIPA1  SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence.    Conclusion  This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S) to Phe (F)) changes a hydrophilic residue (S) to a hydrophobic residue (F) and may significantly alter the protein functions of  SIPA1  in breast tumourgenesis.  SIPA1  SNPs rs931127 (5' near gene), and rs746429 (synonymous (Ala (A) to Ala (A)), did not show significant associations with breast cancer incidence, yet were associated with lymph node metastasis in the previous study. This suggests that  SIPA1  may be involved in different stages of breast carcinogenesis and since this study replicates a previous study of the associated SNP, it implicates variants of the  SIPA1  gene as playing a potential role in breast cancer.

Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility