Sunday, May 18, 2025
5/18/2025
Roles of gut-breast axis in breast pathophysiology - Microbiome impacts cancer development and therapeutic efficacy. In addition to the guts, microbes reside in different tissues influencing the pathophysiology of the tissue microenvironment. These tissue-resident microbes are largely attributed to translocation of gut microbes. In the breast, such passage is termed ‘gut- breast axis’, helping establish microbiotas of breast tissue and milk. Nevertheless, gut-breast axis has been mostly conceptualized around pregnancy, and it is completely unknown whether this axis indeed exists outside pregnancy to impact breast health and carcinogenesis. Our long-term goal is to dissect how microbiome contributes to breast pathophysiology. Especially, the objectives of the present study are to determine i) whether gut-breast axis occurs on a regular basis; ii) whether this involves discrete sets of bacteria for healthy cohorts vs. cancer patients, and iii) what are their roles. Our central hypothesis is that gut-breast axis takes place on a regular basis, involving distinct sets of bacteria to confer anti-tumor effects on healthy cohorts vs. pro-tumor effects on cancer patients. The proposed research is based on our preliminary studies allowing us to harvest specific gut microbiotas from tumor-protected or -susceptible animals. We reported that supplementing sepiapterin (SEP)—the endogenous precursor of tetrahydrobiopterin (the cofactor of nitric oxide (NO) synthase)—normalized arginine metabolism and improved the immunogenicity of HER2-positive mammary tumors. We then orally applied SEP to mice prone to HER2-positive mammary tumors and saw strong tumor prevention. These mice also showed increases in NO levels and NO-producing bacteria in the guts. Besides, extracts of these gut bacteria activated innate immune cells, suggesting the roles of these gut bacteria in anti- tumor immunity. Here, we will determine whether these gut bacteria physically translocate to the breast to exert tumor preventative effects. Our hypothesis will be tested through two SPECIFIC AIMS: 1) Determine whether gut microbiotas of a) tumor-protected vs. b) -susceptible mice exert anti-tumor vs, pro-tumor effects; and 2) determine whether distinct sets of gut microbes are translocated to mammary glands to exert anti-tumor vs. pro-tumor effects. In Aim 1, we will transplant gut microbiota of a) tumor-protected (SEP-treated) or b) - susceptible (DMSO-treated) HER2 mice into recipients and give the inverse drug treatments. We will test whether the transplanted microbiotas antagonize the treatments. In Aim 2, gut microbiota of a) tumor-protected (SEP) vs b) -susceptible (DMSO) mice are differentially labeled, and the 50:50 mixture is given to the recipients undergoing SEP or DMSO treatment. Labeled microbes are analyzed for their gut-breast translocation; their ratios in the breast; and the contributions of breast microbiota to the drug effects. The proposed study is innovative because this is the first time to corroborate gut-breast axis and its contributions to breast pathophysiology. The study is significant because it will have a positive translational impact by justifying the development of a new breast cancer treatment or prevention strategy focused on breast microbiota.
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