breast cancer research • mcb as pre-med - The School of Molecular ...

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daVId shaPIro While it was known before that breast cancer cells have some way of dodging the immune system, it was Professor of Biochemistry in MCB and Professor of Basic Medical Sciences at the College of Medicine David Shapiro who showed that estrogen contributes to that process. In cells containing the ER, the complex of estrogen and ER protein binds to specific DNA sequences to stimulate the production of proteins involved in most breast cancers’ growth and evasion of the immune system. “Since there already are good pharmaceuticals, such as tamoxifen, that work by competing with estrogens for binding to the receptor, we wanted to target other binding sites on the ER,” Shapiro says. Using high-throughput screening techniques, Shapiro’s laboratory was able to identify a compound that slowed the production of proteins that promote the growth of ER-positive breast cancer cells. This compound works by triggering breast cancer cells to destroy ER protein, blocking the action of estrogen, and preventing the growth of cancer cells. This process stops the growth of breast cancer cells that contain ER — even those that are resistant to tamoxifen — and has little effect on other cell types. In an important cell culture test of the new compound in a system in which breast cancer cells form colonies that resemble minitumors, the compound completely blocked colony formation. The next steps are testing the compound in an animal model, and identifying how it triggers the cells to destroy ER protein. Drug development, a new direction for Shapiro’s lab, capitalizes on the recent establishment of a screening center by Shapiro and several faculty members. With its robotic instruments and library of 170,000 compounds, the screening facility plays a key role in the lab’s ability to rapidly test and identify new compounds with promising anti-cancer activity. Shapiro notes that MCB has a national and international reputation for its community of experts looking at breast cancer from a variety of directions. “We have lots of first-hand technical knowledge that we share, which makes doing experiments a lot easier,” he says. 8 . mcb “Undergraduate pre-med students Kenneth Berg and Amanda Etheridge are working to identify the chemical structures that make a compound a specific inhibitor of estrogen receptor in breast cancer cells.”—David Shapiro on two of the students who work in his lab
“the thing I’ve come to value about the MCB curriculum is the emphasis on problem solving skills. I took away a great deal of knowledge about biology, but the ability to think through complex ideas has helped me succeed more...”— Dan thorngren, MCB graduate, former Nardulli Lab Research Specialist, medical school student ann nardullI In an effort to better understand just how the DNA-bound ER regulates gene expression, Professor of Molecular and Integrative Physiology Ann Nardulli isolated and identified proteins associated with that complex. Among the 200 proteins Nardulli identified, she found a group of oxidative stress response proteins, which are responsible for reducing the level of reactive oxygen species in cells. At normal levels, reactive oxygen species are useful for signaling and maintaining a cell’s normal environment, but too much can damage proteins, lipids, and DNA. Nardulli also found another group of proteins that repair DNA. If DNA is damaged and, for example, the DNA repair proteins are under-expressed, DNA might not be efficiently repaired. Nardulli began to think that the over- or under-expression of the oxidative stress response or DNA repair proteins might be involved in the development and/or progression of breast cancer. “We wondered, if we looked at normal mammary tissue, benign hyperplasia, ductal carcinoma in situ, and invasive breast cancer, would we see a difference in the expression of these proteins?” says Nardulli. Nardulli’s group looked at the expression of 12 different proteins in 96 breast biopsies to see if there was a pattern of over- or underexpression of any of the proteins. Nardulli has some very intriguing findings so far. For example, a DNA repair protein that is expressed in normal breast tissue is not expressed in invasive breast cancer tissue. “That seems to be a dangerous situation if a protein required for DNA repair is no longer present to repair damaged DNA,” she says. This also ties in with other observations Nardulli has made about how some of these proteins, which are normally found in the nucleus of normal cells, end up outside the nucleus in tumor cells. “If you change the location of proteins that normally reside in the nucleus so they no can no longer access DNA or reduce their expression, you can accumulate DNA damage. That is one way cancer might occur or progress.” • Photographs of Sligar, Shapiro, Nardulli, and Luthra by Nick Burchell SCHOOL OF MOLECULAR AND CELLULAR BIOLOGY . 9
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