Inhibition of Microbial Beta-Glucuronidase as a Strategy Toward Breast Cancer Chemoprevention
Abstract
Breast cancer is the most common cancer to afflict women, and it is the second leading cause of cancer death. While improvements in diagnosis and therapeutics have greatly increased the survival of patients with breast cancer, there is significant morbidity in those afflicted by this disease. The best approach is then to cure or cure by preventing the development of breast cancer itself. Of the modifiable risk factors for breast cancer (hormone intake, obesity, alcohol as examples) ultimately all have a common theme -- increase in body estrogen burden. It has been demonstrated from decades of human epidemiologic and rodent studies that estrogen can drive breast cancer development in postmenopausal women. Indeed, this risk is directly a result of sustained high burden of active estrogen present in the body. Research has also demonstrated that estrogen in our bodies is significantly broken down into products called metabolites (some are good, others not so good with regards to breast cancer); however, these are eventually further changed into products called "conjugates" that allow our bodies to get rid of estrogen. A major mechanism that allows for estrogen to reactivate involves enzymes produced by our intestinal bacteria called beta-glucuronidase (BGUS for short). BGUS breaks down estrogen glucuronide conjugates (products destined for removal from the body) and causes accumulation of the active metabolites of estrogen in the intestines, which are then absorbed into the body. This allows for keeping the estrogen burden high in the body. Our hypothesis, based on the literature evidence provided, is that by specifically blocking bacterial BGUS, we may prevent the development of estrogen receptor-responsive breast cancer. To test this hypothesis, we have developed a completely new class of chemicals that block the activity of bacterial BGUS enzyme. These chemicals spare mammalian BGUS activity. So these chemicals are highly specific and do not have any side effects when tested in mice. We have a prototype chemical we call Inh1, which we will use to test our hypothesis in mice. To test whether Inh1 prevents breast cancer development in mice, we will use the Polyome MT mouse, developed here at Albert Einstein College of Medicine. These mice develop breast carcinoma through a series of progressive steps transitioning from abnormal breast tissue growth to adenomas to invasive cancers in more than 60% of the mice. In the early stages, there is a marked increase in estrogen receptor in the tumors, making this an attractive and relevant model to study how estrogen exposure drives the formation of early breast cancer. If our project is successful, the concepts will eventually benefit the vast majority of women who are at risk for developing breast cancer, especially those who have modifiable risks such as prolonged use of hormones and/or diets that increase fecal BGUS levels (e.g., high fat diets). The next steps will involve the study of Inh1 in other models of breast cancer and when the clinical formulation and safety of Inh1 is determined, application to humans in short-term (estrogen metabolism) and long-term (prevention) studies. The time frame of this proposal is 3 years; however, we anticipate that short-term human studies with a lead BGUS inhibitor will be conducted within that period given that there is an ongoing effort to formulate these as drugs for clinical studies. The overarching challenge addressed by this project is in prevention of breast cancer (primary prevention) as well as identifying whether BGUS has a significant role in driving early breast cancer. This question has been speculated upon but is unproven. Furthermore, providing scientific evidence in rodents and eventually in humans will provide factual information driving major consumer and patient advocate websites that actively promote BGUS inhibition as a means to prevent breast cancer. Since estrogen metabolism is a key factor in breast
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710023
Entities
People
- Sridhar Mani
Organizations
- Albert Einstein College of Medicine
- United States Army