부산대학교 도서관

Simple Summary: Triple-negative breast cancer (TNBC) is a highly aggressive tumor with a poor prognosis and limited treatment options. Finding new approaches to improve TNBC outcomes and response to treatment is critical. Using the 4T1 murine TNBC model, we show the effect of neoadjuvant chemotherapy in modulating gut microbiota contents. In addition, gut microbiota could be used in the future as a predictive biomarker for doxorubicin responsiveness. Modulating gut microbiota through antibiotics, diet-derived fecal microbiota transplantation, or by exogenous LPS administration impact tumor growth, response to treatment, and metastasis formation. Therefore, harnessing gut microbiota contents could be considered a promising approach in affecting triple-negative breast cancer responsiveness to chemotherapy treatment. Triple-negative breast cancer (TNBC) is highly aggressive with a poor 5-year survival rate. Targeted therapy options are limited and most TNBC patients are treated with chemotherapy. This study aimed to determine whether doxorubicin (Dox) shifts the gut microbiome and whether gut microbiome populations influence chemotherapeutic responsiveness. Female BALB/c mice (n = 115) were injected with 4T1-luciferase cells (a murine syngeneic TNBC model) and treated with Dox and/or antibiotics, high-fat diet-derived fecal microbiota transplant (HFD-FMT), or exogenous lipopolysaccharide (LPS). Metagenomic sequencing was performed on fecal DNA samples. Mice that received Dox were stratified into Dox responders or Dox nonresponders. Mice from the Dox responders and antibiotics + Dox groups displayed reduced tumor weight and metastatic burden. Metagenomic analysis showed that Dox was associated with increased Akkermansia muciniphila proportional abundance. Moreover, Dox responders showed an elevated proportional abundance of Akkermansia muciniphila prior to Dox treatment. HFD-FMT potentiated tumor growth and decreased Dox responsiveness. Indeed, lipopolysaccharide, a structural component of Gram-negative bacteria, was increased in the plasma of Dox nonresponders and FMT + Dox mice. Treatment with exogenous LPS increases intestinal inflammation, reduces Dox responsiveness, and increases lung metastasis. Taken together, we show that modulating the gut microbiota through antibiotics, HFD-FMT, or by administering LPS influenced TNBC chemotherapy responsiveness, lung metastasis, and intestinal inflammation. [ABSTRACT FROM AUTHOR]