Investigating the Roles of Pregnane X Receptor in Human Breast Cancers

Purpose/Study Summary

Breast cancer is the second most common type of cancer diagnosed worldwide and is also the second leading cause of cancer related deaths among women overall While much progress has been made in the diagnosis and treatment of breast cancer, traditional chemotherapeutic treatments can lead to the development of chemotherapeutic resistance and remains a major challenge in overall patient outcomes The activation of the Pregnane X Receptor ( by numerous endo and xenobiotics, including several chemotherapeutic drugs, is known to regulate many of the metabolic pathways associated with drug metabolism and resistance Our long term goal is to understand the transcriptional and metabolic targets of PXR in human breast cancers, and to apply this knowledge in their treatment to improve patient outcomes Our hypothesis, which is formulated on PXR’s known roles in drug metabolism in healthy and pathogenic tissues, is that PXR activation increases xenobiotic metabolism via the induction of Phase I and II enzymes, as well as Phase III transporters, in addition to alterations in the cell cycle and apoptosis in breast cancer We have developed multiple constructs for the expression of human Pregnane X Receptor hPXR in vitro in human breast cancer cell lines Following transfection of each construct, we have verified the expression of exogenous hPXR mRNA, as well as PXR protein Functional analysis of the exogenous hPXR was demonstrated through qRT PCR of known hPXR target genes following PXR activation with rifampicin The next phase will include 1 studying the transcriptome of human breast cancer cells following exogenous hPXR activation in both transfected and non transfected human breast cancer cell lines using RNA Seq and 2 determining the effects of hPXR expression and activation in human breast cancer subtypes on cell cycle progression, cell viability, apoptosis, cell motility, and tumor invasiveness At the successful completion of this project, we expect to gain new insights into the function of the Pregnane X Receptor within in vitro human breast cancer cell lines, and to have identified novel gene expression changes associated with its role(s) in acquired chemoresistance and cell cycle changes.