Development of a Novel Therapeutic Paradigm Utilizing a Mammary Gland-Targeted, Bin 1-Knockout Mouse Model
Abstract
Bin1 is implicated to be anti-cancer gene in mammary gland epithelial cells. We have discovered that Bin1 loss can promote tumorigenesis through a cell-extrinsic mechanism that involves escape from host cell-mediated anti-tumor immunity. This correlates with the negative regulatory impact that Bin1 exerts on the important immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). We have demonstrated how, in combination with certain standard chemotherapeutic agents, inhibitors of IDO can be successfully employed in a non-obvious therapeutic regimen to successfully treat established tumors in MMTV-Neu mice -- an autochthonous breast cancer model histologically akin to ductal carcinoma in situ (DCIS). We have shown that these tumors respond to IDO inhibitor treatment in combination with certain chemotherapeutics, but do not know if this is due to inhibiting IDO that is directly expressed in the tumor cells or in accessory antigen presenting cells (APCs). The studies we are conducting directly interrogate the role of Bin1 loss and concomitant IDO upregulation in the development of autochthonous breast tumors. To this end, we have developed antibodies that will allow us to immuno-histochemically evaluate Bin1 and IDO expression in tumors. Furthermore, we have developed a conditional Bin1 knockout mouse, which will allow us to target Bin1 deletion specifically to the mammary gland epithelium. In conjunction with the bioavailable inhibitor 1-methyl-tryptophan (1MT), we are using a combination of genetic and chemical genetic approaches to establish the pathophysiological relevance of this pathway to mammary gland tumor biology and begin to elucidate the cellular mechanisms by which tumors escape immune rejection.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2006
- Accession Number
- ADA452686
Entities
People
- Alexander J. Muller