Inflammation-associated cancers of the colon, prostate, and breast have increased dramatically during the past 30 years in Westernized countries resulting in a public health crisis. Concomitantly, health advancements including sterile births and widespread use of antibiotics have led to increasingly hygienic living conditions. We speculate that modernized living practices contribute to gastrointestinal (GI) tract imbalances, which in turn result in inflammatory disorders - such as allergy and asthma - and later in life, inflammation-associated cancers. We have already shown in mouse models that GI tract bacteria modulate growth of cancer in extra-intestinal tissues such as mammary and prostate glands. Here, we aim to understand interactions between GI tract microbiome and breast tumor stromal cells. Partnered with parent U54 grant of Timothy C Wang, MD, this collaborative U01 will build upon our earlier findings relating to breast cancer development. We propose a combination of high-throughput immunology, microbiome analyses and gnotobiotic mouse technologies to elucidate specific mechanisms. We have assembled a world-class team of scientists and physicians uniquely poised to carry out this multi-disciplinary research. We predict that remedies to restore GI tract immune balance will be an effective and practical approach to prevent and treat extra-intestinal malignancies such as breast cancer.