Investigating the Roles of Pregnane X Receptor in Human Breast Cancers - Project Summary/Abstract
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 (PXR) by
numerous endo- and xeno-biotics, including several chemotherapeutic drugs, is known to regulate
many of the metabolic pathways associated with drug metabolism and resistance. The 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 in order to improve patient outcomes. The objective
of this application is to elucidate the effects of PXR expression and activation on the transcriptome
and phenotypic changes in human breast cancer cell lines. The central hypothesis, which is
formulated on PXRs known roles in drug metabolism in healthy and pathogenic tissues as well
as preliminary data, 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. The rationale for the proposed research is that once the
transcriptional and phenotypic alterations in response to PXR activation are identified,
pharmacological agents or regimes that interfere with these pathways could be developed to
decrease the chemoresistance of breast cancer. The objective of this project will be
accomplished by two specific aims: (1) Identify global gene expressions changes in human breast
cancers associated with pregnane x receptor expression and/or transcription factor activation. An
RNA-seq based approach will be used to identify changes to the transcriptome in response to
endogenous and exogenous PXR expression and activation. (2) Examine the effects of PXR
expression and activation in models of breast cancer on cell survival and chemoresistance. In-
vitro based assays examining the effects of PXR on various aspects of the cell cycle, survival,
apoptosis, and invasiveness will be utilized. This study is innovative because it shifts the focus
of PXRs roles from normal liver and intestinal drug metabolism in order to fill a large void in our
understanding of PXRs influence on breast cancer, and potentially in many other types of cancer
as well. The proposed project is significant because it will uncover genes and metabolic pathways
that are critical to the development of chemotherapeutic resistance in breast cancer, identifying
new potential therapeutic targets.
