Prostate cancer (PCa) is the most common visceral neoplasm and the second leading cause of cancer-related deaths in male of western societies. Low circulating vitamin D levels and reduced expression of its receptor (VDR) correlate with PCa risk and severity, but the clinical use of vitamin D is limited by its pro-calcemic activities. To characterize the role of VDR in PCa, Pten(i)pe-/- mice, that recapitulate the human disease and in which the tumor suppressor gene Pten is selectively inactivated in prostatic epithelial cells (PECs) at adulthood, were compared to Pten/Vdr(i)pe-/- mice in which PECs are PTEN and VDR-deficient. Histological analysis showed that prostatic intraepithelial neoplasia (PIN) are formed between 1-3 months after gene inactivation (AGI). Importantly, VDR-deficiency increased by 2-fold the PECs proliferation rate as early as 1-month AGI. At this stage, RNA-seq and immunohistochemistry analysis revealed the presence of oxidative DNA damage selectively in VDR-deficient PINs. Moreover, a 4-week supplementation with the antioxidant N-acetyl cysteine reduced oxidative DNA damage in Pten/Vdr(i)pe-/- prostates, and normalized the number of Ki-67+ cells to the levels of Pten(i)pe-/- ones. After 3 months AGI, both Pten(i)pe-/- and Pten/Vdr(i)pe-/- tumors entered in a latency phase characterized by cellular senescence. However, the prostate weight in Pten/Vdr(i)pe-/- mice was 2-fold higher than in Pten(i)pe-/- mice 12 months AGI. In addition, tumors of Pten(i)pe-/- were mostly composed of non-invasive PIN-like adenocarcinoma, whereas invasive adenocarcinoma, sarcomatoid and squamous-cell carcinoma were observed in those of Pten/Vdr(i)pe-/- mice. Immunophenotyping revealed a higher infiltration of neutrophils, also termed as myeloid-derived suppressive cells and implicated in metastasis dissemination, in Pten/Vdr(i)pe-/- prostates compared to Pten(i)pe-/- ones 9 months AGI. Moreover, pan-cytokeratin-positive micro-metastasis were detected in lymph nodes and livers of Pten/Vdr(i)pe-/- mice, but not in those of Pten(i)pe-/- mice. The treatment with CXCR1/CXCR2 receptors inhibitor (SX-682), reduced neutrophils recruitment and micro-metastasis prevalence in Pten/Vdr(i)pe-/- mice. Thus, VDR signaling exerts a protective role on PTEN-deficient PECs by limiting the oxidative-stress and proliferation during PINs initiation, as well as reducing neutrophils recruitment and cancer cell dissemination.