Breast cancer is the most common cancer among women and is the most common cause of cancer death in women. Breast cancer is often considered to be one of the more chemo responsive solid tumour. Many structurally diverse cytotoxic drugs can induce remissions in previously untreated breast cancer patients. However, an important limitation associated with this anticancer drugs use is the unpredictable inter individual variability in efficacy and toxicity.The active form of vitamin D (1,25(OH)2D3) has long been known for its role as an anticancer agent. The vitamin D receptor VDR is a critical component of the vitamin D pathway and over 470 of common single nucleotide polymorphisms have been identified. These polymorphisms modulate the activity of the VDR.Here we show how individual genetic variants could be associated with a good or poor Vitamin D treatment outcome.We first investigated the polymorphic Cdx2 VDR status, the VDR transcript and protein basal expression levels in ER-positive (MCF7, T47D and ZR751) and in ER-negative (MDA-MB-231, SUM159PT, SK-BR3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) breast cancer cell lines. We found high levels of VDR transcript and protein levels in all the ER-positive breast cell lines and in ER-negative breast cell lines with Cdx2 genotype AA.Vitamin D inhibits growth of ER-positive breast cancer cells. In contrast, it has not effect on the ER-negative breast cancer cells which represent a less differentiated, more aggressive breast cancer phenotype. Thus, we focused our attention on the association of Cdx2 VDR polymorphism and response to treatment of Vitamin D on the ER-negative breast cancer cell lines. In these cell lines, we observed that response to Vitamin D varied across different VDR polymorphisms. In particular, cells with Cdx2 genotype AA were more responsible to Vitamin D compared to cells with genotype AG/GG.Subsequently, we decided to explore Cdx2 VDR polymorphism in a set of breast cancer cases of our Institute We considered the potential relationship among Cdx2 VDR polymorphisms and a number biomarkers used in clinical management of breast cancer. We found a statistically significant relation between Cdx2 VDR polymorphism and the presence/absence of estrogen receptor.