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Review
. 2016 Apr 22;108(8):djw029.
doi: 10.1093/jnci/djw029. Print 2016 Aug.

The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer

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Free PMC article
Review

The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer

Maryann Kwa et al. J Natl Cancer Inst. .
Free PMC article

Abstract

The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 10(11) bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor-positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.

Figures

Figure 1.
Figure 1.
The estrobolome and enterohepatic circulation of estrogens. Estrogens are primarily produced in the ovaries, adrenal glands, and adipose tissue and circulate in the bloodstream in free or protein-bound form and first undergo metabolism in the liver, where estrogens and their metabolites are conjugated. Conjugated estrogens are eliminated from the body by metabolic conversion to water-soluble molecules, which are excreted in urine or in bile into the feces. The conjugated estrogens excreted in the bile can be deconjugated by bacterial species in the gut with beta-glucuronidase activity (constituents of the ‘estrobolome’), subsequently leading to estrogen reabsorption into the circulation. Circulating estrogens exert effects on target tissues including breast, which stimulate cellular growth and proliferation. By modulating the enterohepatic circulation of estrogens, the estrobolome affects both the excretion and circulation of estrogens. In turn, the composition of the estrobolome can be shaped by factors such as antibiotics, other drugs, and diet that modulate its functional activity. Adapted from Plottel SC, Blaser MJ. Microbiome and malignancy. Cell Host Microbe. 2011;10(4):324-335.
Figure 2.
Figure 2.
Potential impact of the estrobolome on estrogens. Forms of endogenous estrogen (E) including E2 (estradiol) and E1 (estrone), estrogen metabolites such as hyroxylated moieties, and exogenous estrogens are relevant to breast tissue carcinogenesis. Estrogens act as signaling molecules via several pathways including canonical paths (alpha and beta receptors) and noncanonical mechanisms. Receptors for estrogen are widely distributed in tissues. Estrogen circulates both freely and protein bound. In the liver, estrogens undergo E2 and E1 interconversion and first pass metabolism. Hepatic conjugation of estrogen allows for biliary excretion of conjugated estrogen and conjugated estrogen metabolites into the gastro-intestinal tract where beta-glucuronidases, glucosidases, and hydroxysteroid dehydrogenases of bacterial origin (the estrobolome fraction of the microbiome) regenerate “free” forms of those molecules. The entero-hepatic circulation therefore contributes to plasma levels of estrogens and their metabolites. An estrobolome enriched in bacteria whose enzymatic activity is higher in deconjugative and hydroxylating function would lead to greater relative levels of circulating free estrogens.
Figure 3.
Figure 3.
Potential link of the gut estrobolome and breast cancer risk. The estrobolome/microbiome modulates levels of circulating estrogens and thereby the endogenous hormonal milieu, which can affect the risk of hormone-driven malignancies including breast and endometrial cancer directly or indirectly, for instance via immunomodulation. Higher deconjugating activity in the gut may lead to higher relative plasma levels of estrogen and metabolites, potentially increasing cancer risk, whereas either lower deconjugating activity may have opposite effects. Conversely, the microbiome is modulated by factors such as the environment, host variables, and possibly sex steroid levels.

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