Inhibition of Microbial Beta-Glucuronidase as a Strategy Towards Breast Cancer Chemoprevention
Abstract
The current view of breast cancer development is that estrogen in its active form is a driver of the disease. It is now well established that the estrogens produced by our bodies are broken down and altered in our livers and intestines to what is termed as conjugated metabolites. These conjugated metabolites are formed by the action of enzymes in our bodies that act to dispose of active estrogens from our bodies. In the intestines, however, a very important enzyme system made by bacteria called beta-glucuronidases (BGUS), converts the excreted conjugated metabolites back to active estrogen-like molecules. The newly formed molecules are reabsorbed by into our bloodstream. In this manner, we constantly keep a threshold of active estrogen. We hypothesize that if we block bacterial BGUS using very specific inhibitors (those that will not affect human BGUS enzymes), we could with maximum safety prevent converting excreted estrogen back to its active form. This, we believe, will prevent breast cancer by reducing the amount of active estrogen were absorb each day. This hypothesis while compelling has never been tested before. In 2010, our group in collaboration with the University of North Carolina(Redinbo Laboratory) was the first to report on a first-in-class E. coli specific BGUS inhibitor, which has low availability in the bloodstream (limited to the intestines) and not toxic to bacteria, mouse and human cells. We now have the technical ability to inhibit microbial BGUS enzymes in rodents that would allow us to test whether this strategy reduces the incidence and/or delays the occurrence of breast cancer in rodents. To test the concept, we have chosen a well characterized mouse model of breast cancer, PyMT (Polyoma Middle T). In this model, the breast tissue progresses from normal to hyperplasia to adenoma in an estrogen-receptor-dependent manner.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2020
- Accession Number
- AD1108369
Entities
People
- Sridhar Mani
Organizations
- Albert Einstein College of Medicine