Modulating the Breast Microbiome to Prevent ER+ Breast Cancer
Abstract
The human body contains more bacterial cells than human cells. While the majority of the bacteria biomass is contained to the intestinal track, microbes in lower abundance have been identified in other organ types located distal to the gut, including the mammary gland. A breast tumor microbiome has been identified. We previously demonstrated that diet can shift the mammary gland microbiome. Consumption of a Mediterranean diet increased breast Lactobacillus abundance when compared with non-human primates consuming a Western diet. Literature indicates that women that have malignant breast cancer (BC) have decreased Lactobacillus populations in the tumor adjacent mammary gland tissue when compared with breast tissue from women with benign lesions, implicating microbiota in mediating possible anti-cancer signaling. Menopause was shown to shift the gut microbiome. Literature indicates that postmenopausal women display decreased gut bacterial diversity when compared to body mass index (BMI)-matched premenopausal women. These gut microbial effects are similar to the effects of obesity on gut microbiome. Postmenopausal women also had higher levels of pro-inflammatory IL-6 and MCP-1, suggesting key interactions between estrogen, microbiota, and inflammation. We suggest that menopause regulates mammary gland microbiota populations that promote estrogen receptor positive [ER+] breast tumorigenesis and that tamoxifen administration may shift these bacterial populations to prevent breast cancer and potentiate antiestrogen responsiveness. Our Breakthrough Level 2 application addresses four different Overarching Challenges including: Prevent primary BC; identify determinants of BC risk; identify what drives BC growth; and revolutionize treatment regimens. The purpose of this study is to investigate whether estrogens (menopause, estrogen replacement therapy, or tamoxifen) modulate mammary gland microbiota and microbial-modified metabolites. We will validate our non-human primate findings with breast tumors from neoadjuvant tamoxifen-treated patients and untreated breast tumors from tumor bank registry at Wake Forest University Comprehensive Cancer Center. Furthermore, we aim to determine the impact of mammary gland microbiota and bile acid metabolites on aromatase activity, estrogen bioavailability, and localized gland inflammation. Once we establish the role of breast microbes in facilitating these signaling pathways, we can determine the impact of mammary gland microbiota in ER+ breast tumorigenesis and tamoxifen responsiveness. Moreover, we can design effective combinatorial therapeutic and interventional approaches to shift mammary gland bacteria to increase responsiveness. Successful completion of these aims will determine the physiological role of mammary gland microbiome in breast tumor endocrine therapy responsiveness and recurrence. Long-term goals include development of a clinical trial to target breast microbiota in patients undergoing adjuvant endocrine therapy to increase therapeutic response to ultimately reduce breast cancer mortality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010014
Entities
People
- Katherine Cook
Organizations
- United States Army
- Wake Forest University