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Herbert L. Carter Fellowship recipient Abhinav Luthra (Abhi), a 2nd year Ph.D. student in Biochemistry and member of the Sligar lab, uses a high performance liquid chromatography column to isolate individual proteins from a group. “The better you understand the properties of an enzyme that make it unique, the better you can manipulate its function specifically,” says Abhi about the diagnostic tools used to study one of the enzymes involved in estrogen reception. 6 . mcb stePhen slIgar Director of MCB and I.C. Gunsalus Professor of Biochemistry Stephen Sligar’s lab is taking another approach. He is looking at ways to block the production of estrogen in the breast earlier in the chemical pathway by targeting aromatase, the enzyme that makes estrogen from testosterone and androstenedione. Aromatase is a key pharmaceutical drug target for estrogen responsive breast cancers. By understanding the mechanistic details of this important enzyme, Sligar’s lab hopes to develop a therapeutic that blocks aromatase’s estrogen-making activity in cancer cells without causing a systemic loss of estrogen. This would provide an improvement, in terms of efficacy and specificity, over current aromatase inhibitors in the market — letrozole, anastrozole and exemestane — thereby minimizing the side effects associated with the current generation of therapies. However, “studying this enzyme is very difficult because once you isolate it from the membrane, it’s usually dead,” says Sligar. In a major step forward, Sligar’s lab created an environment that keeps the enzyme functioning. This so-called Nanodisc technology is a nanoscale membrane environment that helps maintain full functionality of the protein. “If you understand how the enzyme works, and there are mechanistic details distinct from similar enzymes, you can design a better, more targeted, drug,” says Sligar. With graduate student Abhinav Luthra, Sligar has discovered that this appears to indeed be the case with aromatase. The Sligar lab is now using this knowledge to design the next generation of pharmaceuticals.
“...the most beneficial aspect of the MCB major was...the myriad of opportunities outside the classroom, particularly the research labs. My participation in Dr. Bagchi’s research helped me gain a better understanding of these lecture topics while developing critical thinking skills needed to help carry out some of his research.” —David Roh; former Bagchi Lab undergrad researcher; Rush University Medical College student, Chicago MIlan bagchI Professor of Molecular and Integrative Physiology Milan Bagchi has investigated the estrogen-regulated genes controlling the growth of breast cancer cells as well as normal mammary epithelial cells (epithelial cells are a common tissue found throughout the body). His lab has identified a gene, ERG1 (abbreviation for “estrogen regulated gene 1,” also known as cuzd1), that, when inactivated in the mouse genome, prevents the proliferation of mammary epithelial cells. This gene is turned on during puberty, when the mammary gland is developing rapidly in response to estrogen. In the absence of this gene, the mammary gland does not develop properly, and the females cannot lactate. “These findings suggest a mammary gland defect when this gene is lacking,” says Bagchi. His lab also found a link between ERG1 and the epidermal growth factor signaling pathways, which are crucial to the growth of cells and involved in many breast cancers. “We have a factor that controls estrogen mediated proliferation, and it serves as a novel connection between hormone regulation and the growth factor pathway,” he says. Bagchi then looked at human breast cancer cells to see if a homologue to the ERG1 gene was present. He found that the ERG1 gene expression correlated with ER status in breast cancer. Strikingly, he found that an over-expression of ERG1 in mammary epithelium results in stimulation of growth factor pathways and tumor formation in mice. Bagchi is now interested in whether this gene can be used as a biomarker of breast tumorigenesis, and is currently collaborating with clinical scientists to screen human breast tumor biopsies to see whether the expression of this gene is elevated in breast cancer. If there is a correlation, Bagchi hopes to use it as a diagnostic tool, and then to develop a therapeutic approach targeting the expression or function of ERG1. “We’ll see if we can intervene in the progression of the tumor,” he says. SCHOOL OF MOLECULAR AND CELLULAR BIOLOGY . 7
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