UM/Sylvester Researchers Identify Molecular Pathway That May Help Fight Breast Cancer
Researchers at the University of Miami Sylvester Comprehensive Cancer Center have identified how an important growth control mechanism is disabled in cancers – and have successfully restored its function in the lab. The research promises to eventually help restore the effectiveness of some breast cancer drugs in cancers that have become drug-resistant.
Joyce M. Slingerland, M.D., Ph.D., F.R.C.P.(C), Director of the Braman Family Breast Cancer Institute at the University of Miami Sylvester Comprehensive Cancer Center, identified how a key growth inhibitor protein is switched off, allowing cancer to proliferate and spread. “Our work solves a big puzzle in this field that has been around for almost 10 years,” said Slingerland.
A growth inhibitor, p27, normally holds the kinase, cyclin E-Cdk2, in check, to prevent cells from starting a new round of DNA synthesis that would lead to cell division. Thus, p27 essentially keeps the brakes on cell division. Slingerland’s group has shown that Src, an oncogene first identified more than 30 years ago, can inactivate p27, leading to its destruction, and switch on cyclin E-Cdk2. A majority of human cancers, including ovarian, prostate, colon, lung and breast, have reduced levels of the p27 growth inhibitor protein. The mystery was how a kinase specifically constrained by p27 could suddenly turn the tables and destroy its own inhibitor. “The conundrum was solved by our recent findings that, early on after growth factors and estrogen give the cell the go signal to divide, Src is turned on, and Src then binds to p27 and causes the inhibitor to lose its inhibitory function,” Slingerland said.
The gene Src is switched on by several factors, including two that are important in breast cancers – human epidermal growth factor receptor 2 (HER2), and estrogen. This latest work by the Braman Family Breast Cancer Institute at UM/Sylvester provides new insights into how estrogen and HER2 contribute to breast cancer growth. Estrogen and HER2 are known to activate Src. Slingerland’s work now links Src to loss of the p27 growth inhibitor, or loss of the “brakes” on cell division. “Src is known to not only promote the survival of cancer cells, it also promotes increased motility that can lead to metastasis,” said Slingerland, a professor of medicine at the UM Miller School of Medicine. “This work provides a brand new understanding of the mechanism whereby Src activates cancer cells to grow and divide.”
Slingerland and her colleagues looked at tamoxifen-resistant breast cancer cell lines in the lab. They found that four out of six of these cell lines had high levels of Src and low levels of p27. They decided to combine tamoxifen with an experimental drug to inhibit Src that is being developed by a pharmaceutical company. “When we combined this Src inhibitor with tamoxifen, we found that the resistant cells that had particularly high levels of Src were completely corrected and their sensitivity to tamoxifen was restored,” she said.
“Then the question was whether we could show that this relationship exists in human breast cancer tissues,” said Slingerland. “So we stained 482 human breast cancers for p27 and tested if tumors that had low p27 might also be the ones with activated Src. We were gratified to find that indeed, in the human breast tumors, low p27 was correlated with high Src activity.”
Almost a decade ago, Dr. Slingerland was among the first in the nation to recognize the relationship between reduced levels of p27 and poor outcome for women with breast cancer. A variety of tumors with reduced levels of p27, not just breast cancers, don’t respond well to therapy. Experimental Src inhibitor drugs promise to give oncologists a new tool to fight these tumors – especially estrogen-responsive breast cancer.
Slingerland’s next step is to begin a clinical trial combining a Src inhibitor with tamoxifen or aromatase inhibitors. Two recent honors awarded to Dr. Slingerland, a highly-prestigious Doris Duke Distinguished Clinical Scientist Award, and a grant from the Breast Cancer Research Foundation, will support the work.
The study is published in the January 26 issue of the journal Cell, http://www.cell.com/.
UM/Sylvester opened in 1992 to provide comprehensive cancer services and today serves as the hub for cancer-related research, diagnosis, and treatment at the University of Miami Leonard M. Miller School of Medicine. UM/Sylvester handles 1,400 inpatient admissions annually, performs 3,000 surgical procedures, and treats 3,000 new cancer patients. All UM/Sylvester physicians are on the faculty of the Miller School of Medicine, South Florida’s only academic medical center. In addition, UM/Sylvester physicians and scientists are engaged in 200 clinical trials and receive more than $31 million annually in research grants. UM/Sylvester at Deerfield Beach opened in 2003 to better meet the needs of residents of Broward and Palm Beach counties. This 10,000 square-foot facility at I-95 and S.W. 10th Streetoffers appointments with physicians from six cancer specialties, complementary therapies from the Courtelis Center, and education and outreach events.