Item Details

title

MANIPULATING THE MICROBIOME TO ENHANCE ICB RESPONSIVENESS AND IMPROVE BREAST CANCER OUTCOMES

author

Clear, Kenysha Yvonnie-Jules

abstract

Globally among women breast cancer (BC) is the most diagnosed cancer type. BC subtype classification at the molecular level, where the association with hormone receptor+ (HR+) expression for estrogen (ER), progesterone (PR) and the overexpression of human-epidermal growth factor 2 (HER2), are key determining factors in assessing patient prognosis and therapeutic course of action. Triple-negative breast cancers (TNBCs), lacking HR+ expression, account for 10-15% of all invasive BC diagnoses, are one of the most aggressive subtypes of BC, and have limited treatment options. HR+ BCs account for 70-80% of all invasive BC diagnoses and have an increased risk of development in postmenopausal, obese patients. In the gut, the microbiome, including specific commensal bacteria and bacterial-derived metabolites, can serve as adaptable targets for enhancing response to ICB therapy in cancer. The breast microbiome has distinct microbial communities that are associated with breast cancer risk. To our knowledge, it is unknown the role of the gut microbiome in modifying TNBC progression and ICB therapy responsiveness. Additionally, the role of the breast microbiome in obesity-mediated postmenopausal breast cancer risk is unknown. Therefore, to determine the role of the gut microbiome in modifying TNBC progression and ICB responsiveness, female syngeneic TNBC tumor-bearing mice were treated with anti-PD-L1 ICB therapy and at least one form of gut microbial modulation, including dietary, fecal microbiota transplantation, probiotics, or postbiotic administration. Results suggest that harnessing the gut microbiome to increase the levels of gut Akkermansia muciniphila or circulating SCFA metabolite propionate can potentially enhance TNBC primary tumor responsive to ICB immunotherapy. To determine the role of the breast microbiome in obesity-mediated postmenopausal breast cancer risk, 16s rRNA was performed on non-cancerous breast samples from patients undergoing breast reduction mammoplasty surgery or lean and obese, pre- and post-menopausal patients undergoing a mastectomy. Results suggest that increased body mass in postmenopausal obese women shifts the breast microbiome diversity, increasing levels of breast tissue Akkermansia muciniphila that leads to a tumor promoting breast microenvironment in HR+ BC. Taken together, these results suggest the potential role of manipulating certain bacterial species and associated-derived metabolites to reduce breast cancer risk and enhance therapeutic responsiveness.

subject

Breast Cancer

Immunotherapy

Microbiome

Tumor Microenvironment

contributor

Cook, Katherine L (advisor)

Pardee, Timothy S (committee member)

Soto-Pantoja, David R (committee member)

Watabe, Kounosuke (committee member)

Miller, Lance D (committee member)

date

2025-06-24T08:36:44Z (accessioned)

2025 (issued)

degree

Physiology and Pharmacology (discipline)

embargo

2027-06-23 (terms)

2027-06-23 (liftdate)

identifier

http://hdl.handle.net/10339/111067 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation