Cecal microbiota and mammary gland microRNA signatures are related and modifiable by dietary flaxseed with implications for breast cancer risk

Abstract

ABSTRACT The gut microbial ecosystem underlies physiological relationships between the gut and distal organs. Mechanisms remain elusive but rely at least partially on the production of a diverse set of absorbable metabolites and host gene expression regulation. Here we show that in female mice, gut cecal microbiota profiles are related to microRNAs (miRNAs) expressed in the mammary gland. A subset of these miRNAs were found to regulate genes involved in breast cancer-related processes, such as cell proliferation and migration. To determine if these relationships could be exploited toward the reduction of breast cancer risk, we studied if they are modifiable by dietary flaxseed (FS), a source of lignan secoisolariciresinol diglucoside (SDG) and alpha-linolenic acid (ALA)-rich oil (FSO), both with antitumor effects. Importantly, SDG, but not ALA, needs microbial processing to release bioactive metabolites. We found that the microbiota and mammary gland miRNA are related, and FS modifies these relationships toward an antioncogenic phenotype. FSO- and SDG-related miRNAs were found to be involved in different pathways and neither FSO nor SDG alone could recapitulate the effects of whole FS, affecting unique pathways related to extracellular matrix processing. These findings highlight the existence of inter-organ microbiota-miRNA relationships, show that dietary interventions interact to affect them, and suggest a novel route for breast cancer prevention. IMPORTANCE Breast cancer is a leading cause of cancer mortality worldwide. There is a growing interest in using dietary approaches, including flaxseed (FS) and its oil and lignan components, to mitigate breast cancer risk. Importantly, there is recognition that pubertal processes and lifestyle, including diet, are important for breast health throughout life. Mechanisms remain incompletely understood. Our research uncovers a link between mammary gland miRNA expression and the gut microbiota in young female mice. We found that this relationship is modifiable via a dietary intervention. Using data from The Cancer Genome Atlas, we also show that the expression of miRNAs involved in these relationships is altered in breast cancer in humans. These findings highlight a role for the gut microbiome as a modulator, and thus a target, of interventions aiming at reducing breast cancer risk. They also provide foundational knowledge to explore the effects of early life interventions and mechanisms programming breast health.