Abstract 6525: Intestinal vitamin D receptor deficiency changes the tumor-associated microbiome in a breast cancer model

Abstract Background: Vitamin D / Vitamin D Receptor (VDR) signaling is regulated by several factors: environmental, host, and microbial. Dysregulation in VDR signaling increases breast cancer risk. Intestinal VDR deletion in mice alters the microbiome, increases intestinal permeability, and promotes growth and bacterial infiltration of breast tumors. Dysbiosis also occurs in breast cancer. Several depleted intestinal bacteria (ex. H. biformis) and tumor bacteria (Lactobacilli and Pseudomonas) are thought to exert anti-tumor effects. The factors that cause these bacterial shifts and their exact contribution to cancer remain unclear. We hypothesize that VDR deficiency predisposes to breast cancer by depleting tumor suppressive bacteria from the intestine and tumor. Methods: To test our hypothesis, we conditionally deleted the VDR in intestinal epithelial cells (VDRΔIEC) of mice with 7, 12-dimethylbenzanthracene (DMBA)-induced breast cancer. A separate group was administered a cocktail of probiotic bacteria to evaluate if the dysbiosis caused by VDR deletion could be reversed. The intestinal and tumor microbiomes were studied using 16S rRNA sequencing of feces (VDRLoxp and VDRΔIEC mice +/- probiotics) and tissue samples (VDRLoxp and VDRΔIEC mice). To validate our findings, we pooled three studies of the human breast microbiome and performed hypothesis testing after batch correction to identify bacteria altered in breast cancer. Results: Many bacterial genera (51) and species (10) had significantly (q<=0.05) different abundances in the intestines of the VDRΔIEC mice relative to VDRLoxp mice, including depletion of the genera Lactobacilli and Pseudomonas. Within the probiotic control group, VDR deletion also significantly (q= 0.014) depleted F. rodentium, the mouse analog to H. biformis. Administration of probiotics did not rescue the depletion of F. rodentium or any other altered bacteria except for Candidatus Arthromitus. We further found that the breast tumor microbiomes from VDRΔIEC mice were significantly different from those of the VDRLoxp mice with 12 differentially abundant bacterial species (2 enriched / 10 depleted). These include depletion of Lactobacilli species (L. johnsonii, L. reuteri, and L. intestinalis) and Pseudomonas species (P. azotoformans, P. fluorescens, or P. synxantha) from the breast tumor microenvironment. Our analysis of public data showed that the genera Lactobacilli and Pseudomonas are both significantly (q<=0.05) depleted in human breast tumors relative to tissue from healthy patients. Conclusions: Intestinal VDR deficiency alters the bacteria in the intestines and breast tumors of DMBA mice. The Vitamin D / VDR signaling dependent beneficial microbiome may contribute to the prevention of breast cancer pathogenesis. Further studies are needed to validate these findings and evaluate if this mechanism can be targeted to prevent or treat breast cancer. Citation Format: Duncan J. Claypool, Yong-guo Zhang, Yinglin Xia, Jun Sun. Intestinal vitamin D receptor deficiency changes the tumor-associated microbiome in a breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6525.