HARNESSING THE MICROBIOME TO IMPACT CHEMOTHERAPY RESPONSIVENESS IN TRIPLE-NEGATIVE BREAST CANCER

Abstract

Breast cancer is the most commonly diagnosed cancer among American women. Breast cancer is characterized into different molecular subtypes according to receptor expression. Triple-negative breast cancer (TNBC) comprises 15-20% of breast cancer cases, affecting young women, presents with aggressive tumors, and is associated with a poorer prognosis. Due to the lack of receptors expression, treatment of TNBC is limited, and chemotherapy-based regimens are the standard of care. The human body co-exists with approximately 100 trillion microbial cells called microbiota, and each organ has its characteristic collection of microbes. The majority of the bacterial microbiome is contained in the gastrointestinal tract. Homeostasis between the host and the microbial entities should be maintained for normal body functioning, and any disruption of this balance may promote disease, including breast cancer. This dissertation aims to determine whether doxorubicin administration shifted the gut microbiome and whether gut microbiota populations correlate with chemotherapeutic responsiveness that could be a predictive biomarker associated with outcome. Breast tumor microbiome has been identified. We aim to determine whether neoadjuvant chemotherapy modulates the tumor microbiome and evaluate the impact of microbes on breast cancer signaling. Metagenomics analysis of gut microbiota of doxorubicin treated TNBC murine model showed doxorubicin shifted gut microbiota contents, and certain species were associated with responsiveness. Also, ablating gut microbiota with broad-spectrum antibiotics reduced tumor growth and lung metastasis. Furthermore, high-fat diet-derived fecal microbiota transplant (FMT) shifted gut microbiota distribution, potentiated tumor growth, and decreased doxorubicin responsiveness. Moreover, 16S-rRNA sequencing on human breast tumors showed neoadjuvant chemotherapy shifted tumor microbiota contents and was associated with development of metastasis. Indeed, in vitro studies showed bacterial metabolites could impact breast cancer cells’ signaling and doxorubicin efficacy. Our studies provide insight into chemotherapy effects on the gut and tumor microbiome composition and suggest that gut microbiome could be used as a biomarker for doxorubicin response. We also show modulating microbiota contents through antibiotics or specific bacteria-FMT influences treatment outcomes and metastatic development. The current body of work supports future studies exploring Akkermansia muciniphila supplementation in TNBC patients undergoing neoadjuvant chemotherapy to improve outcomes and potentially reduce intestinal side effects of chemotherapy.