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 UM/Sylvester, 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 ten years,” says 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 says.

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 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. “This work provides a brand-new understanding of the mechanism whereby Src activates cancer cells to grow and divide,” says Slingerland, a professor of medicine at the UM Miller School of Medicine.

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 says.

“Then the question was whether we could show that this relationship exists in human breast cancer tissues,” says 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, Slingerland was among the first researchers to recognize the relationship between reduced levels of p27 and poor outcomes for women with breast cancer. A variety of tumors with reduced levels of p27,