Posted October 24, 2013
Stephen Byers, Ph.D., Georgetown University
Although basal-like breast carcinomas constitute only 10% to 15% of known breast cancers, they are typically aggressive, resistant to hormonal therapy, and consequently associated with poor clinical outcomes. One molecule associated with invasive breast cancers is the cell-cell adhesion protein, E-cadherin. Normally, breast epithelial cells stop growing when they come in close contact with neighboring cells. Changes in cell-cell adhesion contribute to the ability of breast cancer cells to invade surrounding tissue during metastasis. A number of studies have linked decreased expression of E-cadherin to the epithelial-mesenchymal transition that is strongly associated with metastasis.
But E-cadherin loss, while important in cancer progression, may not be sufficient. Funded with a Fiscal Year 2000 (FY00) Idea Award and a FY06 Synergistic Idea Award, both from the BCRP, Dr. Stephen Byers and his colleagues showed that another adhesion molecule, cadherin-11, is also changed in breast cancers. However, unlike E-cadherin, it is not the decrease, but the increase of cadherin-11 expression that is associated with breast cancer. The increase is striking enough that compared to E-cadherin loss, elevated cadherin-11 actually provides an even more powerful predictor of tumor invasion and metastasis.
Continuing to build upon this work on cadherin-11 with funding from a FY09 BCRP Idea Expansion Award, Dr. Byers teamed with Dr. Milton Brown to explore the role of cadherin-11 in basal-type breast cancer. They found that when two splice variants of cadherin-11 - the full-length and truncated forms - are both expressed in the same cell, they cause the cell to exhibit metastatic, invasive behavior. Thus, Dr. Byers and colleagues determined that cadherin-11 was a potential therapeutic target for basal-like breast cancer.
The Byers lab further sought to identify compounds that inhibit cadherin-11 in order to treat basal-like breast cancer. In addition to the design and generation of molecules de novo, the team chose to screen drugs already approved by the FDA, in hopes of finding one that could be brought to the clinic quickly to treat breast cancer patients. Dr. Sivanesan Dakshanamurthy, a computational chemist at Georgetown, created a program that predicted how drugs would interact with potential molecular targets. Interestingly, he found that the arthritis drug Celebrex was among the top drugs with the potential to bind and inhibit cadherin-11.
The finding was published only last year, and it is still too soon to know how effective Celebrex might be in treating basal-like breast cancers, but Dr. Byers is optimistic about his lab's approach: "The prospect of using a drug developed for arthritis in treating breast cancer is very powerful," Dr. Byers said. "The support of the DoD Breast Cancer Research Program was crucial to the success of this work as it allowed us to explore a hypothesis that was high risk and high reward."
Dakshanamurthy S, Issa NT, Assefnia S, Seshasayee A, Peters OJ, Madhavan S, Uren A, Brown ML, and Byers SW. 2012. Predicting new indications for approved drugs using a proteo-chemometric method. J Med Chem 55(15):6832-6848.
Feltes CM, Kudo A, Blaschuk O, and Byers SW. 2002. An alternatively spliced cadherin-11 enhances human breast cancer cell invasion. Cancer Res 62(22):6688-6697.
Public and Technical Abstracts: Targeting Cadherin 11 in Basal-Like, Hormone-Refractory Breast Cancer