Impact of Microbiota Dysbiosis on Breast Carcinogenesis
Abstract
Overarching challenge(s): This study will address the overarching challenges, “identify determinants of breast cancer initiation, risk or susceptibility” and “identify what determines breast cancer growth; determine how to stop it.” What types of patients will it help and how will it help them? Breast cancer remains the leading cause of cancer-related mortality in women worldwide. Approximately 12.4% women in the USA confront invasive breast cancer, and it is estimated that 266,120 women in the USA were diagnosed with invasive breast cancer while 63,960 were diagnosed with carcinoma in situ in 2018. Multiple risk factors have been defined for breast cancer incidence, but it is important to note that a large number of (~70%) of women who develop breast cancer in their lifetime do not carry established familial risk factors. There is an immediate need to “look beyond the usual suspects.” Human microbiome is now referred to as “the forgotten organ” as it contains a metagenome that is 100-fold more diverse than human genome. Humans have coevolved with millions of microorganisms including bacteria harboring different niches in the body. The human gastrointestinal tract carries up to 1,011 bacterial cells per gram of luminal content, whose collective genetic material contains about 100-fold greater number of individual genes than the human genome. Owing to the recent success of the National Institutes of Health-led Human Microbiome Project and standardization of deep sequencing techniques, we are now in a unique position to “look beyond the usual suspects” and ask innovative questions – systematically interrogate the microbiome changes that associate with breast cancer incidence, progression, and clinical response. Our study design: (1) We will analyze fecal and serum samples from women with breast cancer, benign breast disease, and healthy volunteers collected under Johns Hopkins Breast Cancer Program Longitudinal Repository. We will conduct microbiome (fecal samples) and metabolome (serum samples) analyses and correlate it with patient outcomes. We will identify pathogens and metabolites that are important in breast cancer initiation and progression and response to chemotherapy. (2) We already analyzed data from public databases and found the presence of pathogenic Bacteroides fragilis (B. fragilis) in abundance in malignant breast tumors. B. fragilis commonly infects the gut and is identified as a risk factor for colon cancer. Pathogenic B. fragilis produces a toxin called Bacteroides fragilis Toxin (BFT) or fragilysisn, and our preliminary research reveals that BFT induces molecular changes in breast cancer and normal breast cell lines rendering them more aggressive. BFT pretreated cells formed more aggressive tumors in experimental mice, and they exhibited enhanced tumor forming capacity in subsequent generations. The BFT-pretreated tumors also seemed to be supported by a pro-tumor microenvironment. We have designed studies to examine the effect of B. fragilis on breast cancer progression using mouse models. We also plan to examine additional novel pathogens identified in Aim 1 in a “clinic-to-lab” approach. (3) We observed that BFT interferes with chemotherapy efficacy. Hence, we plan to test three strategies to combat the influence of B. fragilis infection and potentiate the efficacy of chemotherapy regimens. Successful completion of these studies can potentially help a large number of patients as infection with B. fragilis is quite prevalent. In epidemiologic studies, pathogenic B. fragilis has been isolated in about 29% of adult diarrhea patients and 38% of inflammatory bowel disease patients. In colon cancer patients, 27%-70% of patients harbor pathogenic B. fragilis. Also, B. fragilis could form a consortium with harmful bacterial species while inhibiting the proliferation of beneficial bacterial species. B. fragilis infection can enhance the risk of breast cancer development in a suscep
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010626
Entities
People
- Dipali Sharma
Organizations
- Johns Hopkins University
- United States Army