Research Finds Functional Link Between Two Causes of Breast Cancer Treatment Failure

A functional link between two major causes of treatment failure in breast cancer has been identified in research from The Cancer Institute of New Jersey (CINJ). The research shows that the protein behind one of these causes plays a role in increasing the drug resistance properties of the other. The work, which investigators say could help to identify targeted therapies, is being presented in abstract form at the Annual Meeting of the American Association for Cancer Research (AACR) being held in Chicago this week. CINJ is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School.

It is well known that drug resistance and the spread of cancer account for most failures of cancer therapy, including therapies for breast and ovarian cancer. While the biology behind each has been studied extensively, it is through this study by lead investigator Lorna Rodriguez, MD, PhD, chief of gynecologic oncology at CINJ, and colleagues, where a functional linkage between drug resistance and cancer spread is shown.

At focus are the P-glycoprotein (P-gp) and CD44 proteins, which influence multidrug resistance and metastases respectively. P-gp is responsible for transporting specific molecules out of the cell thus making cancer cells resistant to chemotherapy. CD44 is a membrane protein that allows for cells to stick to one another and cause cancer to spread. CD44 has also been identified as a stem cell marker for various types of cancer including breast and ovarian cancer.

Previous research by Dr. Rodriguez and colleagues into the role that CD44 plays in ovarian cancer revealed a physical and functional interaction between P-gp and CD44, showing they both purify and stabilize themselves, and are in close proximity to each other in the cell membrane. In this current research, investigators examined breast and ovarian cell lines in laboratory models using an identification method based on a unique yeast protein system that detects interactions between proteins that are embedded into the cell membrane. Rodriguez says the current findings lay the groundwork for future research into the two proteins, including the role they play in reducing the effectiveness of chemotherapy drugs.

Researchers created a mutation within the CD44 protein at residue sites known to switch on or off enzymes that are responsible for numerous cell processes. What they found was when the site known as Ser 291 is mutated, P-gp function is blocked and cells become drug sensitive despite signals from P-gp calling for drug resistance. The team therefore hypothesized that CD44 could be stabilizing P-gp. They determined that P-gp is broken down and made inactive through the removal of the "switch" that turns cellular processes on and off. To prove this, investigators screened a number of enzymes to see if there was one in particular that was causing this reaction. The FBXO21 enzyme, which has no known function yet, was tested and shown to independently inactivate P-gp. When CD44 is introduced, the team demonstrated that it blocks P-gp''s inactivation by FBXO21.

"These findings are key to understanding P-glycoprotein-induced drug resistance and elucidate a new control mechanism of P-glycoprotein activation," noted Rodriguez, who is a professor of obstetrics, gynecology and reproductive sciences at UMDNJ-Robert Wood Johnson Medical School. "With P-gp activated in 60 percent of metastatic breast tumors and CD44 in 80 percent, these findings could have a profound impact on the management of metastatic breast cancer through the development of targeted therapies."

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Along with Rodriguez, other authors include: Abhilash Ravindranath, CINJ; Roman Wernyj, CINJ; Karl Miletti-Gonzalez, CINJ and UMDNJ-Robert Wood Johnson Medical School; Swayamjot Kaur, CINJ; Muthu N. Kumaran, CINJ; et al.

The work was supported by funding from the Department of Defense, the National Cancer Institute, the New Jersey Commission on Cancer Research, the Kaleidoscope of Hope Foundation, and the Philip & Janice Levin Foundation.

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About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state''s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ''s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School. Follow us on Facebook at www.facebook.com/TheCINJ.

The CINJ Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Medical Center, Carol G. Simon Cancer Center at Overlook Medical Center, and Cooper University Hospital. Affiliate Hospitals: CentraState Healthcare System, JFK Medical Center, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), Somerset Medical Center, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate



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