Travis Salisbury, PhD
I have 12 years of experience in studies on regulation of gene expression in response to signaling. My work on regulated gene expression started during my postdoctoral training. My research identified that gonadotropin releasing hormone (GnRH), which signals through a G protein coupled receptor (GPCR), regulates gene expression by activating the transcriptional coactivator β-catenin. Finding that GPCR signaling regulated β- catenin activity was novel, because β-catenin had historically been associated with the developmental Wnt signaling pathway. Currently, I supervise an active laboratory, teach medical and graduate students and I was promoted to associate professor with tenure in 2015. My work remains focused on signal-regulated gene expression. Our recent studies have identified that the aryl hydrocarbon receptor (AHR), which is a ligandactivated transcription factor, responds to and mediates signaling pathways in breast cancer cells including insulin like growth factor 2 (IGF2), tumor necrosis factor (TNF) and adipokines. Evidence that IGF2, TNF, and adipokines signal through AHR is an important shift in its role, considering that AHR is best known for mediating the toxic and gene expression effects of the environmental toxicant TCDD
Our research focus is on signaling mechanisms that control breast cancer. One project investigates targeting nutrient transport to suppress breast cancer in obesity. The premise for this project stems from clinical work showing that obesity significant increases breast cancer mortality, worsens breast cancer outcomes, renders tumors less responsive to cancer therapy and increases the rate of metastatic breast cancer. The signaling mechanisms by which obesity promotes breast cancer progression is an important knowledge gap. We hypothesize that paracrine and endocrine factors released by adipose tissue during obesity induce signaling in breast cancer cells that increases leucine absorption by cancer cells. In addition to being an essential amino acid that is required for protein synthesis, leucine can also induce and sustain oncogenic mTOR signaling in cancer. Thus, suppressing leucine uptake by cancer cells will not only starve tumor cells, but it will also reduce mTOR pathways that promote the growth and metastatic potential of cancer. Others and we have published that L-Type Amino Acid Transporter 1 (LAT1) is a critically important leucine transporter that is overexpressed in breast cancer. Others and we have published that suppressing LAT1 inhibits the growth of breast cancer cells. We have new data showing that adipose tissue secretes factors that induce LAT1 expression and activity in breast cancer cells. We therefore hypothesize that obesity promotes breast cancer by inducing LAT1 expression and activity in breast tumors. We are currently investigating the unique regulation of LAT1 in breast cancer during obesity.
Our second project involves targeting the aryl hydrocarbon receptor (AHR) to suppress breast cancer. The AHR is a ligand activated transcription factor. Others and we have shown that certain AHR ligands inhibit the growth and metastatic potential of breast cancer cells. We recently published that the putative endogenous AHR ligand, ITE, reduces the JAG1-NOTCH1 pathway in triple negative breast cancer (TNBC) cells. The JAG1-NOTCH1 pathway is an embryonic pathway that upon being overactive induces and promotes breast cancer. There are drugs in clinical trials to suppress the JAG1-NOTCH1 pathway for breast cancer therapy. However, our report is the first to show that an AHR ligand suppresses JAG1-NOTCH1 signaling in cancer. This new finding provides mechanistic evidence to suppress JAG1-NOTCH1 signaling in cancer with AHR ligands. We are currently investigating mechanisms by which ITE inhibits breast cancer growth by inhibiting cell cycle and the JAG1-NOTCH1 pathway.